Combined Rituximab and Lenalidomide Treatment for Untreated Patients With Follicular Lymphoma (RELEVANCE)

• ClinicalTrials.gov Identifier: NCT01476787
• Recruitment Status: Active, not recruiting
• First Posted: November 22, 2011
• Last Update Posted: April 12, 2024
• Sponsor: Celgene
• Collaborator: The Lymphoma Academic Research Organisation
• Information provided by (Responsible Party): Celgene

Tracking Information

• First Submitted Date: November 18, 2011
• First Posted Date: November 22, 2011
• Last Update Posted Date: April 12, 2024
• Actual Study Start Date: December 29, 2011
• Estimated Primary Completion Date: April 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 22, 2018)

• Complete Response Rate (CR/CRu) at 120 weeks [ Time Frame: Up to approximately 2.5 years ]
  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.
• Progression free survival (PFS)Follicular lymphoma [ Time Frame: Up to 12 years ]
  Is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause.

Original Primary Outcome Measures (submitted: November 18, 2011)

• Complete response (CR/CRu) rate [ Time Frame: 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. Complete response unconfirmed (CRu) is defined as those patients who fulfill the criteria for CR above but with with indeterminant bone marrow or with residual disease that has decreased in size by greater than 75%.
• Progression free survival (PFS) [ Time Frame: Up to 13 years ]
  Progression-free survival is defined as the time from the start of study drug therapy to the first observation of disease progression or death due to any cause.

Current Secondary Outcome Measures (submitted: April 5, 2016)

• Number of participants with adverse events [ Time Frame: Up to 13 years ]
• Time to Treatment Failure (TTF)Follicular Lymphoma [ Time Frame: Up to 13 years ]
  Time to Treatment Failure (TTF)Follicular Lymphoma
• Number of Participants who Survive without an Event(s) [ Time Frame: Up to 13 years ]
  Event Free Survival (EFS)Follicular Lymphoma
• Time to Next Anti-Lymphoma Treatment (TTNLT) for Follicular Lymphoma [ Time Frame: Up to 12 years ]
  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
• Time to Next Chemotherapy Treatment (TTNCT) for Follicular Lymphoma [ Time Frame: Up to 13 years ]
  Time to Next Chemotherapy Treatment (TTNCT) for Follicular Lymphoma
• Number of participants alive or dead [ Time Frame: Up to 13 years ]
• Overall response by International Working Group (IWG) 1999 criteria [ Time Frame: Up to 120 weeks ]
• Health related quality of life as measured by the EORTC QLQ-C30 for Follicular Lymphoma patients [ Time Frame: Up to 13 years ]
  Health related quality of life as measured by the EORTC QLQ-C30 for Follicular Lymphoma patients
• Event-Free Survival (EFS) [ Time Frame: Up to 12 years ]
  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.
• Overall Survival (OS) [ Time Frame: up to 12 years ]
  Will be measured from date of randomization to the date of death
• Complete Response Rate (CR/CRu) at 120 weeks [ Time Frame: Up to approximately 2.5 years ]
  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.

Original Secondary Outcome Measures (submitted: November 18, 2011)

• Number of participants with adverse events [ Time Frame: Up to 13 years ]
• Time to Treatment Failure (TTF) [ Time Frame: Up to 13 years ]
• Number of Participants who Survive without an Event(s) [ Time Frame: Up to 13 years ]
  Event Free Survival (EFS)
• Time to Next Anti-Lymphoma Treatment (TTNLT) [ Time Frame: Up to 13 years ]
• Time to Next Chemotherapy Treatment (TTNCT) [ Time Frame: Up to 13 years ]
• Number of participants alive or dead [ Time Frame: Up to 13 years ]
• Overall response by International Working Group (IWG) 1999 criteria [ Time Frame: 120 weeks ]
• Health related quality of life as measured by the EORTC QLQ-C30 [ Time Frame: Up to 13 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combined Rituximab and Lenalidomide Treatment for Untreated Patients With Follicular Lymphoma
• Official Title: 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
• Brief Summary: 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.

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Follicular Lymphoma

Intervention

• 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 Name: Revlimid
• 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.

Study Arms

• 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.
  Interventions:

  • Drug: Rituximab
  • Drug: Lenalidomide
• 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.
  Interventions:

  • Drug: Rituximab-CHOP
  • Drug: Rituximab-CVP
  • Drug: Rituximab-Bendamustine

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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 28, 2016): 255
• Original Estimated Enrollment (submitted: November 18, 2011): 1000
• Estimated Study Completion Date: April 30, 2024
• Estimated Primary Completion Date: April 30, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan, United States

Administrative Information

• NCT Number: NCT01476787
• Other Study ID Numbers: RV-FOL-GELARC-0683C; 2011-002792-42 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Celgene
• Original Responsible Party: Celgene Corporation
• Current Study Sponsor: Celgene
• Original Study Sponsor: Celgene Corporation
• Collaborators: The Lymphoma Academic Research Organisation

Investigators

• Study Chair: Franck Morschhauser, MD, PhD; The Lymphoma Study Association (LYSA)

• PRS Account: Celgene
• Verification Date: April 2024