Clinical trial NCT01938001: Rituximab Plus Lenalidomide for Patients With Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma (Follicular Lymphoma and Marginal Zone Lymphoma)
Official title: A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Rituximab Plus Lenalidomide (CC-5013) Versus Rituximab Plus Placebo in Subjects With Relapsed/Refractory Indolent Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lymphoma, Non-Hodgkin
Keywords: Non-Hodgkins Follicular lymphoma, Non-Hodgkins Marginal zone lymphoma, treatment for follicular lymphoma, treatment for Marginal zone lymphoma
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2013-09-10
Enrollment: 358
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This double-blind randomized, parallel group study will evaluate the efficacy and safety of lenalidomide (Revlimid, CC-5013) in combination with rituximab (MabThera/Rituxan) in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma. Patients will be randomized to receive either lenalidomide or placebo for twelve 28-day cycles in combination with rituximab. Anticipated time on study treatment is 1 year.

Detailed description: Indolent lymphoma is a slow growing but incurable lymphoma which includes follicular lymphoma and marginal zone lymphoma. Follicular lymphoma and marginal zone lymphoma are cancers of the B lymphocyte, a type of white blood cell. Lenalidomide is an immunomodulatory drug (a drug that affects the immune system) which alters the body's immune system and it may also interfere with the development of tiny blood vessels involved in tumor growth. Therefore, lenalidomide may reduce or prevent the growth of cancer cells. Lenalidomide has also been shown to restore the immune cells' ability to attack and kill tumor cells, an ability that may be inhibited by follicular lymphoma and other lymphomas. The combination of rituximab and lenalidomide may eliminate the cancer while restoring the immune system's ability to attack tumor cells.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years at the time of signing the informed consent document.
* Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
* Histologically confirmed marginal zone lymphoma or follicular lymphoma (grade 1, 2 or 3a; CD20+ by flow cytometry or histochemistry).
* Previously treated with at least one prior systemic chemotherapy, immunotherapy or chemoimmunotherapy and have received at least 2 previous doses of rituximab.
* Documented relapsed, refractory or progressive disease after treatment with systemic therapy and must not be rituximab-refractory.
* Investigator considers rituximab monotherapy appropriate.
* Bi-dimensionally measurable disease on cross sectional imaging by X-ray computed tomography (CT) or magnetic resonance imaging (MRI).
* Need of treatment for relapsed, progressed or refractory disease as assessed by the investigator.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Adequate bone marrow function.
* Willingness to follow study visit schedule, pregnancy precautions and other protocol requirements.

Exclusion Criteria:

* Histology other than follicular or marginal zone lymphoma or clinical evidence of transformation or Grade 3b follicular lymphoma.
* Subjects taking corticosteroids during the last week prior to study treatment, unless administered at a dose equivalent to \< 20 mg/day prednisone or prednisolone.
* Systemic anti-lymphoma therapy within 28 days or use of antibody agents within 8 weeks use of radioimmunotherapy within 6 months.
* Known seropositive for or active viral infection with hepatitis B virus (HBV) or/and human immunodeficiency virus (HIV).
* Known hepatitis C virus (HCV) positive with chronic HCV or active viral infection with HCV hepatitis requiring anti-viral medication (at time of randomization).
* Life expectancy \< 6 months.
* Known sensitivity or allergy to murine products.
* Prior history of malignancies, other than follicular or marginal zone lymphoma, unless the subject has been free of the disease for ≥ 5 years.
* Prior use of lenalidomide.
* Known allergy to thalidomide.
* Neuropathy \> Grade 1.
* Presence or history of central nervous system involvement by lymphoma.
* Subjects who are at a risk for a thromboembolic event and are not willing to take prophylaxis for it.
* Uncontrolled intercurrent illness.
* Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent document.
* Pregnant or lactating females.
* Any condition that places the subject at unacceptable risk if he/she were to participate in the study or that confounds the ability to interpret data from the study.

Primary outcomes:
measure: Kaplan Meier Estimate of Progression Free Survival Assessed by the Independent Review Committee (IRC) According to the 2007 International Working Group Response Criteria (IWGRC)
timeFrame: From randomization of study drug up to disease progression or death, which occurred first; up to the data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).
Secondary outcomes:
measure: Durable Complete Response Rate (DCCR) as Assessed by the IRC According to the 2007 IWGRC
timeFrame: From first dose of investigational product (IP) to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomiade arm and 11.04 months in the rituximab/placebo arm
measure: Kaplan-Meier Estimate of Overall Survival (OS)
timeFrame: From date of randomization to death due to any cause (Average of 55.71 months and a maximum up to 95.2 months)
measure: Percentage of Participants With an Objective Response as Assessed by the IRC According to the 2007 IWGRC
timeFrame: From date of first dose to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomide arm and 11.04 months in the rituximab/placebo arm
measure: Percentage of Participants With a Best Response of Complete Response as Assessed by the IRC According to the 2007 IWGRC
timeFrame: From date of first dose up to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomide arm and 11.04 months in the rituximab/placebo arm
measure: Kaplan-Meier Estimate of Duration of Objective Response as Assessed by the IRC According to the 2007 IWGRC
timeFrame: From randomization up to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).
measure: Kaplan-Meier Estimate of Duration of Complete Response (DOCR) as Assessed by the IRC According to the 2007 IWGRC
timeFrame: From randomization up to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).
measure: Kaplan Meier Estimate of Event Free Survival as Assessed by the IRC According to the 2007 IWGRC
timeFrame: From date of randomization to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).
measure: Kaplan Meier Estimate of Time to Next Anti-Lymphoma Treatment (TTNLT)
timeFrame: From date of randomization to date of first documented administration of a new anti-lymphoma treatment (Average of 55.71 months and a maximum up to 95.2 months)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first dose to 28 days post last dose (Average of 55.71 months and a maximum up to 95.2 months)
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Mitchell Cancer Center, University of South Alabama
state: Alabama
city: Glendale
country: United States
facility: Arizona Center for Cancer Care
state: Arizona
city: Escondido
country: United States
facility: Southwest Cancer Care Medical Group
state: California
city: Greenbrae
country: United States
facility: Marin Oncology Associates
state: California
city: La Verne
country: United States
facility: Wilshire Oncology Medical Group, Inc
state: California
city: Oceanside
country: United States
facility: North County Hematology Oncology (NCHO) - TRM, LLC.
state: California
city: Orange
country: United States
facility: Hematology-Oncology Medical Group of Orange County, Inc.
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Santa Maria
country: United States
facility: Central Coast Medical Oncology Corporation
state: California
city: West Hills
country: United States
facility: Wellness Hematology Oncology
state: California
city: Southington
country: United States
facility: Cancer Center of Central Connecticut
state: Connecticut
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists North Region Sarah Cannon Research
state: Florida
city: Peoria
country: United States
facility: Illinois Cancer Care, P.C.
state: Illinois
city: Laconia
country: United States
facility: LRG Healthcare Oncology Clinic
state: Indiana
city: Des Moines
country: United States
facility: Iowa Oncology Research Association
state: Iowa
city: Louisville
country: United States
facility: University of Louisville, J.G. Brown Cancer Center
state: Kentucky
city: Southfield
country: United States
facility: Providence Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Cloud
country: United States
facility: Coborn Cancer Center at the St. Cloud Hospital
state: Minnesota
city: Hooksett
country: United States
facility: NH Oncology - Hematology, PA
state: New Hampshire
city: Hackensack
country: United States
facility: The Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Morristown
country: United States
facility: Hematology-Oncology Associates of Northern NJ
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Cincinnati
country: United States
facility: Oncology Hematology Care Sarah Cannon Research
state: Ohio
city: Portland
country: United States
facility: Local Institution - 028
state: Oregon
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Greenville
country: United States
facility: St Francis Hospital
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Regional Healthcare System - Gibbs Cancer Center & Research Institute
state: South Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Inst
state: Tennessee
city: Arlington
country: United States
facility: Arlington Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Tacoma
country: United States
facility: Northwest Medical Specialties PLLC
state: Washington
city: Brugge
country: Belgium
facility: AZ St-Jan Brugge Oostende AV
city: Gent
country: Belgium
facility: Local Institution - 371
city: Gent
country: Belgium
facility: UZ Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge
city: Yvoir
country: Belgium
facility: CHU Mont -Godinne
city: Porto Alegre
country: Brazil
facility: Associacao Hospitalar Moinhos de Vento Hospital Moinhos de Vento
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da PUCRS
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Associacao Educudora Sao Carlos AESC Hospital Giovanni Battista HGB Hospital Mae de Deus Center
state: Rio Grande Do Sul
city: Barretos
country: Brazil
facility: Fundacao Pio XII - Hospital de Cancer de Barretos
state: São Paulo
city: Jau/SP
country: Brazil
facility: Hospital Dr. Amaral Carvalho/ Hospital Amaral Carvalho Jaú
state: São Paulo
city: Rio De Janeiro
country: Brazil
facility: MS INCA HC I Hospital do Cancer I
city: São Paulo
country: Brazil
facility: Sociedade Beneficente de Senhoras Hospital Sirio Libanes
city: São Paulo
country: Brazil
facility: Real e Benemerita Associacao Portuguesa de Beneficencia
city: São Paulo
country: Brazil
facility: Fundação Antonio Prudente - AC Camargo Câncer center
city: Beijing, PR
country: China
facility: Beijing Cancer Hospital
city: Beijing
country: China
facility: Peking University People's Hospital
city: Beijing
country: China
facility: 307 Hospital of PLA
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Changsha
country: China
facility: The Third Xiangya hospital of central south university
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
city: Guangzhou
country: China
facility: Guangdong General Hospital
city: Guangzhou
country: China
facility: Local Institution - 600
city: Hangzhou City
country: China
facility: The First Affiliated Hospital of Medical School of Zhejiang University
city: Hangzhou City
country: China
facility: Local Institution - 604
city: Nanjing
country: China
facility: Jiangsu Province Hospital The First Hospital affiliated with Nanjing Medical University
city: Shanghai
country: China
facility: Cancer Hospital, Fudan University
city: Shanghai
country: China
facility: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
city: Tianjin
country: China
facility: Chinese Academy of Medical Sciences & Peking Union Medical College
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute and Hospital
city: Xi'an
country: China
facility: Xijing Hospital
city: Brno
country: Czechia
facility: Interni hematoonkologicka klinika
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove, IV.interni hematologicka klinika
city: Ostrava
country: Czechia
facility: Fakultni Nemocnice Ostrava, Klinika hematoonkologie,
city: Prague 10
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady, Interni hematologicka klinika
city: Praha
country: Czechia
facility: Local Institution - 534
city: Praha
country: Czechia
facility: Vseobecna Fakultni Nemocnice v Praze
city: Angers
country: France
facility: CHU d'Angers
city: Bobigny Cedex
country: France
facility: Centre Hospitalier Universitaire d'Avicennes
city: Brest Cedex
country: France
facility: CHRU de Brest - Hopital Morvan
city: Paris
country: France
facility: Hopital Saint-Louis
city: Perpignan
country: France
facility: CH Perpignan - Hopital Saint-Jean
city: Poitiers
country: France
facility: CHU de Poitiers
city: Valence
country: France
facility: Centre Hospitalier de Valence
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin Charité - Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin Campus Virchow Klinikum
city: Frankfurt
country: Germany
facility: Krankenhaus Nordwest
city: Leer
country: Germany
facility: Onkologische Schwerpunktpraxis Leer - Emden
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf GmbH
city: Villingen-Schwenningen
country: Germany
facility: Klinkum der Stadt Villingen-Schwenningen GmbH
city: Beer Sheva
country: Israel
facility: Soroka University Medical Center
city: Jerusalem
country: Israel
facility: Hadassah University Hospital
city: Tel-Aviv
country: Israel
facility: Tel-Aviv Sourasky Medical Center
city: Aviano (PN)
country: Italy
facility: Centro di Riferimento Oncologico - IRCCS
city: Barletta
country: Italy
facility: U.O.C. Ematologia
city: Bologna
country: Italy
facility: A.O.U. di Bologna Policlinico S.Orsola-Malpighi
city: Catania
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi - Nesima
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori (I.R.S.T.)
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia - IEO
city: Milano
country: Italy
facility: Ospedale Niguarda Ca Granda
city: Napoli
country: Italy
facility: IRCCS- Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"
city: Palermo
country: Italy
facility: Az. Osp. Vincenzo Cervello
city: Palermo
country: Italy
facility: Casa di Cura La Maddalena
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di Parma
city: Ravenna
country: Italy
facility: Ospedale di Ravenna
city: Reggio Calabria
country: Italy
facility: Azienda Ospedaliera Bianchi-Melacrino-Morelli
city: Rimini
country: Italy
facility: Ospedale degli Infermi di Rimini
city: Roma
country: Italy
facility: Azienda Ospedaliera S. Andrea - Università La Sapienza
city: Roma
country: Italy
facility: Local Institution - 340
city: Nagasaki-shi
country: Japan
facility: Local Institution - 708
state: Nagasaki
city: Minato-ku
country: Japan
facility: Local Institution - 709
state: Tokyo
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Hiroshima
country: Japan
facility: Chugoku Central Hospital
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
city: Kobe-city
country: Japan
facility: Kobe City Medical Center General Hospital
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of Japanese Foundation For Cancer Research
city: Koto-ku
country: Japan
facility: Local Institution - 700
city: Kyoto-city
country: Japan
facility: University Hospital, Kyoto Prefectural University of Medicine
city: Minato-ku
country: Japan
facility: Toranomon Hospital
city: Nagasaki
country: Japan
facility: The Japanese Red Cross Nagasaki Genbaku Hospital
city: Nagoya
country: Japan
facility: Nagoya Medical Center,Division of Hematology/Oncology
city: Sendai-shi
country: Japan
facility: National University Corporation Tohoku University, Tohoku University Hospital
city: Kraków
country: Poland
facility: Malopolskie Centrum Medyczne S.C.
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii w Warszawie
city: Warszawa
country: Poland
facility: Local Institution - 514
city: Warszawa
country: Poland
facility: Centrum Onkologii, Instytut im. Marii Sklodowskiej-Curie
city: Warszawa
country: Poland
facility: Local Institution - 513
city: Lisboa
country: Portugal
facility: Instituto Portugues de Oncologia de Lisboa, Francisco Gentil
city: Lisboa
country: Portugal
facility: Local Institution - 330
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia do Porto, Francisco Gentil
city: Porto
country: Portugal
facility: Local Institution - 331
city: San Juan
country: Puerto Rico
facility: Hospital Auxilio Muto Centro de Cancer
city: Krasnoyarsk
country: Russian Federation
facility: Krasnoyarsk Regional Clinical Hospital
city: Moscow
country: Russian Federation
facility: Russian Academy of Medical Sciences Institution
city: Moscow
country: Russian Federation
facility: Moscow State Medical Institution Municipal Clinical Hospital n.a. S.P. Botkin
city: St Petersburg
country: Russian Federation
facility: Federal Centre of Heart, Blood and Endocrinology of Rosmed technlologies V.A. Almazov
city: St.Petersburg
country: Russian Federation
facility: St. Petersburg Pavlov State Medical University
city: Tula
country: Russian Federation
facility: The Ministry of Health and Social Development of the Tula region state institution Health Tula regio
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Córdoba
country: Spain
facility: Local Institution - 314
city: Madrid
country: Spain
facility: Hospital Universitario Infanta Leonor
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Marbella
country: Spain
facility: Hospital Costa del Sol
city: Marbella
country: Spain
facility: Local Institution - 315
city: Murcia
country: Spain
facility: Hospital Morales Meseguer
city: Murcia
country: Spain
facility: Local Institution - 318
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Salamanca
country: Spain
facility: Local Institution - 311
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Del Rocio
city: Adana
country: Turkey
facility: Cukurova University Medical Faculty Balcali Hospital
city: Ankara
country: Turkey
facility: Hacettepe Universitesi
city: Denizli
country: Turkey
facility: Pamukkale University Medical Faculty
city: Gaziantep
country: Turkey
facility: Gaziantep University
city: Istanbul
country: Turkey
facility: Marmara University
city: Izmir
country: Turkey
facility: Dokuz Eylul University Izmir
city: Samsun
country: Turkey
facility: 19 Mayis Medical Faculty - Samsun
city: Umuttepe Kocaeli
country: Turkey
facility: Kocaeli Derince Training and Research Hospital
city: Eastbourne
country: United Kingdom
facility: Eastbourne District General Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital, Prescot Street
city: London
country: United Kingdom
facility: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square
city: Westcliff on Sea
country: United Kingdom
facility: Southend University Hospital NHS Foundation Trust, Prittlewell Chase
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Leonard JP, Trneny M, Izutsu K, Fowler NH, Hong X, Zhu J, Zhang H, Offner F, Scheliga A, Nowakowski GS, Pinto A, Re F, Fogliatto LM, Scheinberg P, Flinn IW, Moreira C, Cabecadas J, Liu D, Kalambakas S, Fustier P, Wu C, Gribben JG; AUGMENT Trial Investigators. AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2019 May 10;37(14):1188-1199. doi: 10.1200/JCO.19.00010. Epub 2019 Mar 21.