Combined Rituximab and Lenalidomide Treatment for Untreated Patients With 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 in Subjects With Previously Untreated Follicular Lymphoma

The purpose of this study is to evaluate the effect of the combined treatment of lenalidomide and rituximab in controlling the Follicular Lymphoma disease and also increase the length of response compared to the available standard combination chemotherapy treatment for Follicular Lymphoma.

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.

The 'Relevance' cooperative group trial 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 Follicular Lymphoma patients enrolled in both studies will be analyzed.

• Study Type: Interventional
• Enrollment (Actual): 255
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Sendai-city, Japan, 983-8520
    • Local Institution - 41022
  • Tokyo
    • Koto-ku, Tokyo, Japan, 1358550
      • Local Institution - 40222
• United States
  • Michigan
    • Southfield, Michigan, United States, 48075
      • Local Institution - 53003
  • Texas
    • Dallas, Texas, United States, 75246
      • Local Institution - 51203
    • Houston, Texas, United States, 77030
      • Local Institution - 51103
    • Lubbock, Texas, United States, 79410
      • Local Institution - 54003

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed follicular lymphoma grade 1, 2 or 3a, Stage II-IV
• Have no prior systemic treatment for lymphoma
• Symptomatic follicular lymphoma requiring treatment.
• Age ≥18 years
• Eastern Cooperative oncology group performance status 0-2
• Willing to follow pregnancy precautions

Exclusion Criteria:

• Clinical evidence of transformed lymphoma or Grade 3b follicular lymphoma.
• 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), human immunodeficiency virus (HIV)
• Known sensitivity or allergy to murine products.
• Presence or history of central nervous system involvement by lymphoma
• At high risk for a venous thromboembolic event (VTE) and not willing to take VTE prophylaxis
• Any of the following laboratory abnormalities:
• serum aspartate transaminase or alanine transaminase > 3x upper limit of normal (ULN), except in patients with documented liver involvement by lymphoma
• total bilirubin > 2.0 mg/dl (34 µmol/L) except in cases of Gilberts Syndrome and documented liver or pancreatic involvement by lymphoma
• creatinine clearance of < 30 mL/min

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 for 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 up to 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; 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: Lenalidomide; 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; 7 to 8 weeks later responding patients will continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.; Drug: Rituximab-CVP; 7 to 8 weeks later responding patients will continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.; Drug: Rituximab-Bendamustine; 7 to 8 weeks later responding patients will 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 (CR/CRu) at 120 weeks	The tumor response data will be assessed by the IRC using the IWG (Cheson, 1999) criteria. Based on the CT/MRI schedule, any assessments in a time window of 120 weeks ± 4 weeks are qualified as the 120 week assessments.	Up to approximately 2.5 years
Progression free survival (PFS)Follicular lymphoma	Is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause.	Up to 12 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Rate (CR/CRu) at 120 weeks	The tumor response data will be assessed by the IRC using the IWG (Cheson, 1999) criteria. Based on the CT/MRI schedule, any assessments in a time window of 120 weeks ± 4 weeks are qualified as the 120 week assessments.	Up to approximately 2.5 years
Number of participants with adverse events		Up to 13 years
Time to Treatment Failure (TTF)Follicular Lymphoma	Time to Treatment Failure (TTF)Follicular Lymphoma	Up to 13 years
Number of Participants who Survive without an Event(s)	Event Free Survival (EFS)Follicular Lymphoma	Up to 13 years
Time to Next Anti-Lymphoma Treatment (TTNLT) for Follicular Lymphoma	TTNLT will be measured from the date of randomization to the date of first documented administration of any new anti-lymphoma treatment (chemotherapy, radiotherapy, radio immunotherapy, immunotherapy). Patients continuing in response or who are lost to follow-up will be censored on their last visit date. Patients who died (due to any cause) before having received a new anti-lymphoma	Up to 12 years
Time to Next Chemotherapy Treatment (TTNCT) for Follicular Lymphoma	Time to Next Chemotherapy Treatment (TTNCT) for Follicular Lymphoma	Up to 13 years
Number of participants alive or dead		Up to 13 years
Overall response by International Working Group (IWG) 1999 criteria		Up to 120 weeks
Health related quality of life as measured by the EORTC QLQ-C30 for Follicular Lymphoma patients	Health related quality of life as measured by the EORTC QLQ-C30 for Follicular Lymphoma patients	Up to 13 years
Event-Free Survival (EFS)	EFS will be measured from the date of randomization to the date of first documented progression, relapse, and initiation of a new anti-lymphoma treatment or death by any cause. Responding patients and patients who are lost to follow up will be censored at their last tumor assessment date.	Up to 12 years
Overall Survival (OS)	Will be measured from date of randomization to the date of death	up to 12 years

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.
• Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014 Nov;15(12):1311-8. doi: 10.1016/S1470-2045(14)70455-3. Epub 2014 Oct 15.
• Ahmadi T, Chong EA, Gordon A, Aqui NA, Nasta SD, Svoboda J, Mato AR, Schuster SJ. Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. Cancer. 2014 Jan 15;120(2):222-8. doi: 10.1002/cncr.28405. Epub 2013 Oct 7.
• 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.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2011
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: November 18, 2011
• First Submitted That Met QC Criteria: November 18, 2011
• First Posted (Estimated): November 22, 2011

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Follicular lymphoma; Non-Hodgkins Follicular Lymphoma; treatment for Follicular Lymphoma; rituximab treatment; rituximab and lenalidomide treatment
• 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-0683C; 2011-002792-42 (EudraCT Number)