Rituximab Plus Lenalidomide for Patients With Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma (Follicular Lymphoma and Marginal Zone Lymphoma)

Lymphoma, Non-Hodgkin Clinical Trial

— AUGMENT  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01938001
• Other study ID #: CC-5013-NHL-007
• Status: Completed
• Phase: Phase 3
• Start date: November 21, 2013
• Est. completion date: January 26, 2022

Study information

• Verified date: January 2023
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 358
• Est. completion date: January 26, 2022
• Est. primary completion date: June 22, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Non-Hodgkin

Intervention

Drug:
• Rituximab
Rituximab 375mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) on Day 1 of every 28 day cycle from Cycles 2 to 5
• Lenalidomide
Lenalidomide 20mg by mouth (PO) daily on Days 1 to 21 every 28 days up to 12 cycles
• Placebo
Placebo (identical matched capsule) PO daily on Days 1 to 21 every 28 days

Locations

Country	Name	City	State
Belgium	AZ St-Jan Brugge Oostende AV	Brugge
Belgium	Local Institution - 371	Gent
Belgium	UZ Gent	Gent
Belgium	AZ Groeninge	Kortrijk
Belgium	CHU Mont -Godinne	Yvoir
Brazil	Fundacao Pio XII - Hospital de Cancer de Barretos	Barretos	São Paulo
Brazil	Hospital Dr. Amaral Carvalho/ Hospital Amaral Carvalho Jaú	Jau/SP	São Paulo
Brazil	Associacao Educudora Sao Carlos AESC Hospital Giovanni Battista HGB Hospital Mae de Deus Center	Porto Alegre	Rio Grande Do Sul
Brazil	Associacao Hospitalar Moinhos de Vento Hospital Moinhos de Vento	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da PUCRS	Porto Alegre	Rio Grande Do Sul
Brazil	MS INCA HC I Hospital do Cancer I	Rio De Janeiro
Brazil	Fundação Antonio Prudente - AC Camargo Câncer center	São Paulo
Brazil	Real e Benemerita Associacao Portuguesa de Beneficencia	São Paulo
Brazil	Sociedade Beneficente de Senhoras Hospital Sirio Libanes	São Paulo
China	307 Hospital of PLA	Beijing
China	Peking Union Medical College Hospital	Beijing
China	Peking University People's Hospital	Beijing
China	Beijing Cancer Hospital	Beijing, PR
China	The Third Xiangya hospital of central south university	Changsha
China	West China Hospital of Sichuan University	Chengdu
China	Fujian Medical University Union Hospital	Fuzhou
China	Guangdong General Hospital	Guangzhou
China	Local Institution - 600	Guangzhou
China	Sun Yat-sen University Cancer Center	Guangzhou
China	Local Institution - 604	Hangzhou City
China	The First Affiliated Hospital of Medical School of Zhejiang University	Hangzhou City
China	Jiangsu Province Hospital The First Hospital affiliated with Nanjing Medical University	Nanjing
China	Cancer Hospital, Fudan University	Shanghai
China	Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine	Shanghai
China	The First Affiliated Hospital of Soochow University	Suzhou
China	Chinese Academy of Medical Sciences & Peking Union Medical College	Tianjin
China	Tianjin Medical University Cancer Institute and Hospital	Tianjin
China	Xijing Hospital	Xi'an
Czechia	Interni hematoonkologicka klinika	Brno
Czechia	Fakultni nemocnice Hradec Kralove, IV.interni hematologicka klinika	Hradec Kralove
Czechia	Fakultni Nemocnice Ostrava, Klinika hematoonkologie,	Ostrava
Czechia	Fakultni nemocnice Kralovske Vinohrady, Interni hematologicka klinika	Prague 10
Czechia	Local Institution - 534	Praha
Czechia	Vseobecna Fakultni Nemocnice v Praze	Praha
France	CHU d'Angers	Angers
France	Centre Hospitalier Universitaire d'Avicennes	Bobigny Cedex
France	CHRU de Brest - Hopital Morvan	Brest Cedex
France	Hopital Saint-Louis	Paris
France	CH Perpignan - Hopital Saint-Jean	Perpignan
France	CHU de Poitiers	Poitiers
France	Centre Hospitalier de Valence	Valence
Germany	Charite - Universitaetsmedizin Berlin Campus Virchow Klinikum	Berlin
Germany	Charite - Universitaetsmedizin Berlin Charité - Campus Benjamin Franklin	Berlin
Germany	Krankenhaus Nordwest	Frankfurt
Germany	Onkologische Schwerpunktpraxis Leer - Emden	Leer
Germany	Kliniken Maria Hilf GmbH	Mönchengladbach
Germany	Klinkum der Stadt Villingen-Schwenningen GmbH	Villingen-Schwenningen
Israel	Soroka University Medical Center	Beer Sheva
Israel	Hadassah University Hospital	Jerusalem
Israel	Tel-Aviv Sourasky Medical Center	Tel-Aviv
Italy	Centro di Riferimento Oncologico - IRCCS	Aviano (PN)
Italy	U.O.C. Ematologia	Barletta
Italy	A.O.U. di Bologna Policlinico S.Orsola-Malpighi	Bologna
Italy	Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi - Nesima	Catania
Italy	Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori (I.R.S.T.)	Meldola
Italy	Istituto Europeo di Oncologia - IEO	Milano
Italy	Ospedale Niguarda Ca Granda	Milano
Italy	IRCCS- Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"	Napoli
Italy	Az. Osp. Vincenzo Cervello	Palermo
Italy	Casa di Cura La Maddalena	Palermo
Italy	Azienda Ospedaliero-Universitaria di Parma	Parma
Italy	Ospedale di Ravenna	Ravenna
Italy	Azienda Ospedaliera Bianchi-Melacrino-Morelli	Reggio Calabria
Italy	Ospedale degli Infermi di Rimini	Rimini
Italy	Azienda Ospedaliera S. Andrea - Università La Sapienza	Roma
Italy	Local Institution - 340	Roma
Japan	National Cancer Center Hospital	Chuo-ku
Japan	Chugoku Central Hospital	Hiroshima
Japan	National Cancer Center Hospital East	Kashiwa
Japan	Kobe City Medical Center General Hospital	Kobe-city
Japan	Local Institution - 700	Koto-ku
Japan	The Cancer Institute Hospital of Japanese Foundation For Cancer Research	Koto-ku
Japan	University Hospital, Kyoto Prefectural University of Medicine	Kyoto-city
Japan	Local Institution - 709	Minato-ku	Tokyo
Japan	Toranomon Hospital	Minato-ku
Japan	The Japanese Red Cross Nagasaki Genbaku Hospital	Nagasaki
Japan	Local Institution - 708	Nagasaki-shi	Nagasaki
Japan	Nagoya Medical Center,Division of Hematology/Oncology	Nagoya
Japan	National University Corporation Tohoku University, Tohoku University Hospital	Sendai-shi
Poland	Malopolskie Centrum Medyczne S.C.	Kraków
Poland	Centrum Onkologii, Instytut im. Marii Sklodowskiej-Curie	Warszawa
Poland	Instytut Hematologii i Transfuzjologii w Warszawie	Warszawa
Poland	Local Institution - 513	Warszawa
Poland	Local Institution - 514	Warszawa
Portugal	Instituto Portugues de Oncologia de Lisboa, Francisco Gentil	Lisboa
Portugal	Local Institution - 330	Lisboa
Portugal	Instituto Portugues de Oncologia do Porto, Francisco Gentil	Porto
Portugal	Local Institution - 331	Porto
Puerto Rico	Hospital Auxilio Muto Centro de Cancer	San Juan
Russian Federation	Krasnoyarsk Regional Clinical Hospital	Krasnoyarsk
Russian Federation	Moscow State Medical Institution Municipal Clinical Hospital n.a. S.P. Botkin	Moscow
Russian Federation	Russian Academy of Medical Sciences Institution	Moscow
Russian Federation	Federal Centre of Heart, Blood and Endocrinology of Rosmed technlologies V.A. Almazov	St Petersburg
Russian Federation	St. Petersburg Pavlov State Medical University	St.Petersburg
Russian Federation	The Ministry of Health and Social Development of the Tula region state institution Health Tula regio	Tula
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitario Reina Sofia	Córdoba
Spain	Local Institution - 314	Córdoba
Spain	Hospital Universitario Fundacion Jimenez Diaz	Madrid
Spain	Hospital Universitario Infanta Leonor	Madrid
Spain	Hospital Costa del Sol	Marbella
Spain	Local Institution - 315	Marbella
Spain	Hospital Morales Meseguer	Murcia
Spain	Local Institution - 318	Murcia
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Local Institution - 311	Salamanca
Spain	Hospital Universitario Virgen Del Rocio	Sevilla
Turkey	Cukurova University Medical Faculty Balcali Hospital	Adana
Turkey	Hacettepe Universitesi	Ankara
Turkey	Pamukkale University Medical Faculty	Denizli
Turkey	Gaziantep University	Gaziantep
Turkey	Marmara University	Istanbul
Turkey	Dokuz Eylul University Izmir	Izmir
Turkey	19 Mayis Medical Faculty - Samsun	Samsun
Turkey	Kocaeli Derince Training and Research Hospital	Umuttepe Kocaeli
United Kingdom	Eastbourne District General Hospital	Eastbourne
United Kingdom	Royal Liverpool University Hospital, Prescot Street	Liverpool
United Kingdom	Barts Cancer Institute, Queen Mary University of London, Charterhouse Square	London
United Kingdom	Southend University Hospital NHS Foundation Trust, Prittlewell Chase	Westcliff on Sea
United States	University of New Mexico	Albuquerque	New Mexico
United States	Arlington Cancer Center	Arlington	Texas
United States	Oncology Hematology Care Sarah Cannon Research	Cincinnati	Ohio
United States	Iowa Oncology Research Association	Des Moines	Iowa
United States	Southwest Cancer Care Medical Group	Escondido	California
United States	Arizona Center for Cancer Care	Glendale	Arizona
United States	Marin Oncology Associates	Greenbrae	California
United States	St Francis Hospital	Greenville	South Carolina
United States	The Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	NH Oncology - Hematology, PA	Hooksett	New Hampshire
United States	MD Anderson Cancer Center	Houston	Texas
United States	Wilshire Oncology Medical Group, Inc	La Verne	California
United States	LRG Healthcare Oncology Clinic	Laconia	Indiana
United States	University of Louisville, J.G. Brown Cancer Center	Louisville	Kentucky
United States	Mitchell Cancer Center, University of South Alabama	Mobile	Alabama
United States	Hematology-Oncology Associates of Northern NJ	Morristown	New Jersey
United States	Sarah Cannon Research Inst	Nashville	Tennessee
United States	Weill Cornell Medical College	New York	New York
United States	North County Hematology Oncology (NCHO) - TRM, LLC.	Oceanside	California
United States	Hematology-Oncology Medical Group of Orange County, Inc.	Orange	California
United States	Illinois Cancer Care, P.C.	Peoria	Illinois
United States	Local Institution - 028	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	UC Davis Medical Center	Sacramento	California
United States	Coborn Cancer Center at the St. Cloud Hospital	Saint Cloud	Minnesota
United States	Florida Cancer Specialists North Region Sarah Cannon Research	Saint Petersburg	Florida
United States	Central Coast Medical Oncology Corporation	Santa Maria	California
United States	Providence Cancer Institute	Southfield	Michigan
United States	Cancer Center of Central Connecticut	Southington	Connecticut
United States	Spartanburg Regional Healthcare System - Gibbs Cancer Center & Research Institute	Spartanburg	South Carolina
United States	SUNY Upstate Medical University	Syracuse	New York
United States	Northwest Medical Specialties PLLC	Tacoma	Washington
United States	Wellness Hematology Oncology	West Hills	California
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  China,  Czechia,  France,  Germany,  Israel,  Italy,  Japan,  Poland,  Portugal,  Puerto Rico,  Russian Federation,  Spain,  Turkey,  United Kingdom, 

References & Publications (2)

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 Investigat — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Kaplan Meier Estimate of Progression Free Survival Assessed by the Independent Review Committee (IRC) According to the 2007 International Working Group Response Criteria (IWGRC)	Progression-free survival (PFS) was defined as the time from date of randomization into the study to the first observation of documented disease progression or death due to any cause, whichever occurred first. PFS was based on the data from the IRC review using the modified 2007 International Working Group Response Criteria (IWGRC) using FDA censoring rules.	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	Durable Complete Response Rate (DCCR) as Assessed by the IRC According to the 2007 IWGRC	DCCR was defined as the percentage of participants with a best response of complete response (CR) that lasted no less than one year (= 48 weeks) during the study prior to administration of new anti-lymphoma therapy. A CR is defined as a complete disappearance of any disease-related symptoms and normalization of biochemical abnormalities.	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
Secondary	Kaplan-Meier Estimate of Overall Survival (OS)	Overall survival was defined as the time from randomization to death from any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented.	From date of randomization to death due to any cause (Average of 55.71 months and a maximum up to 95.2 months)
Secondary	Percentage of Participants With an Objective Response as Assessed by the IRC According to the 2007 IWGRC	Percentage of participants with an objective response is defined as having a response of at least a PR during the study without administration of new anti-lymphoma therapy. A complete response = a complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of any disease-related symptoms, and normalization of biochemical abnormalities; a partial response (PR) = 50% decrease in SPD of the 6 largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD.	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
Secondary	Percentage of Participants With a Best Response of Complete Response as Assessed by the IRC According to the 2007 IWGRC	Percentage of participants with a best response of at CR during the study without administration of new anti-lymphoma therapy. A CR = Complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of any disease-related symptoms, and normalization of biochemical abnormalities.	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
Secondary	Kaplan-Meier Estimate of Duration of Objective Response as Assessed by the IRC According to the 2007 IWGRC	Duration of response (DOR) was defined as the time from initial response (at least PR) until documented progressive disease (PD) or death. Participants who had not progressed at the time of analysis were censored at the last assessment date that the participant was known to be progression free. Participants who received a new treatment without documented progression were censored at the last assessment date that the participants was known to be progression free.	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).
Secondary	Kaplan-Meier Estimate of Duration of Complete Response (DOCR) as Assessed by the IRC According to the 2007 IWGRC	DOCR was defined as the time from initial CR until documented PD or death. Participants who had not progressed at the time of analysis were censored at the last assessment date that the participant was known to be progression free. Participants who received a new treatment without documented progression were censored at the last assessment date that the participants was known to be progression free.	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).
Secondary	Kaplan Meier Estimate of Event Free Survival as Assessed by the IRC According to the 2007 IWGRC	Event-free survival (EFS) was defined as the time from date of randomization to date of first documented progression, relapse, institution of new anti-lymphoma treatment (chemotherapy, radiotherapy or immunotherapy) or death from any cause. Responding participants and those who were lost to follow up were censored at their last tumor assessment date.	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).
Secondary	Kaplan Meier Estimate of Time to Next Anti-Lymphoma Treatment (TTNLT)	Time to next anti-lymphoma treatment (TTNLT) was defined as the time from date of randomization to date of first documented administration of a new anti-lymphoma treatment (including chemotherapy, radiotherapy, radioimmunotherapy or immunotherapy). The time to the next anti-lymphoma treatment was of special interest to the study.	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)
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs)	TEAEs include AEs that started or worsened between the date of the first dose and 28 days after the date of the last dose. 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 to 28 days post last dose (Average of 55.71 months and a maximum up to 95.2 months)

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