A Study of Rituximab (MabThera) Subcutaneous (SC) Versus Rituximab (MabThera) Intravenous in Participannts With Follicular Non-Hodgkin's Lymphoma

A Two-Stage Phase III, International, Multi-Center, Randomized, Controlled, Open-Label Study to Investigate the Pharmacokinetics, Efficacy and Safety of Rituximab SC in Combination With CHOP or CVP Versus Rituximab IV in Combination With CHOP or CVP in Patients With Previously Untreated Follicular Lymphoma Followed by Maintenance Treatment With Either Rituximab SC or Rituximab IV

This two-stage, multi-center, randomized, controlled, open-label study will investigate the pharmacokinetics, efficacy and safety of rituximab SC versus rituximab IV in participants with previously untreated follicular non-Hodgkin's lymphoma. Participants will be randomized to receive 375 milligrams per meter square (mg/m^2) rituximab as IV infusion or 1400 milligrams (mg) rituximab SC. In addition, participants will receive standard chemotherapy. Participants who achieved a complete or partial response (PR) after 8 treatment cycles, will receive maintenance treatment for a further maximum number of 12 cycles. Maintenance treatment cycles will be repeated every 8 weeks. This is a two-stage study. Stage 1 was designed to confirm the chosen rituximab SC dose resulting in comparable rituximab serum Ctrough levels compared with rituximab IV, when given as part of induction treatment every 3 weeks. Enrollment for Stage 2 started after the rituximab SC dose was established in Stage 1. Stage 2 aimed to further investigate the efficacy and safety of rituximab SC compared with rituximab IV. The anticipated time on study treatment is 96 weeks.

Study Overview

• Status: Completed
• Conditions: Non-Hodgkin's Lymphoma
• Intervention / Treatment: Drug: Rituximab IV; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine; Drug: Prednisone/Prednisolone; Drug: Rituximab SC

• Study Type: Interventional
• Enrollment (Actual): 410
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Gosford, New South Wales, Australia, 2250
      • Gosford Hospital; Cancer Care Services
    • Wollongong, New South Wales, Australia, 2500
      • Wollongong Hospital; Cancer Services
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
    • Southport, Queensland, Australia, 4215
      • Gold Coast Hospital; Haematology Department
  • South Australia
    • Woodville South, South Australia, Australia, 5011
      • Queen Elizabeth Hospital; Haematology
• Belgium
  • Edegem, Belgium, 2650
    • UZ Antwerpen
  • Liège, Belgium, 4000
    • CHU Sart-Tilman
  • Wilrijk, Belgium, 2610
    • Sint Augustinus Wilrijk
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina, 88000
    • University Clinical Center of the Republic of Srpska, Clinic for Internal Disease, Hematology Dept
  • Sarajevo, Bosnia and Herzegovina, 71000
    • University Clinical Center Sarajevo, Clinic for Hematology
  • Tuzla, Bosnia and Herzegovina, 75000
    • University Clinical Centre Tuzla, Clinic for Oncology, Hematology and Radiotherapy
• Brazil
  • MG
    • Belo Horizonte, MG, Brazil, 30140-001
      • Nucleo de Hematologia e Transplante de Medula Ossea de Minas Gerais
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
      • Hospital Sao Lucas - PUCRS
    • Porto Alegre, RS, Brazil, 90035-003
      • Hospital das Clinicas - UFRGS
  • SP
    • Sao Paulo, SP, Brazil, 05403-000
      • Hospital das Clinicas - FMUSP
    • Sao Paulo, SP, Brazil, 01221-020
      • Santa Casa de Misericordia de Sao Paulo; Hematologia e Hemoterapia
• Bulgaria
  • Pleven, Bulgaria, 5800
    • UMHAT Dr Georgi Stranski; Hematology
  • Plovdiv, Bulgaria, 4002
    • Umhat S. George; Hematology
  • Sofia, Bulgaria, 1756
    • Specialised Hospital For Treatment Of Hematological Diseases; Hematology
  • Varna, Bulgaria, 9010
    • Mhat Sveta Marina; Dept. of Haematology
• Canada
  • Quebec, Canada, G1J 1Z4
    • CHU de Quebec - Hopital de l'Enfant-Jesus; Unite de Recherche en Hematologie et Oncologie
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Queen Elizabeth II Health Sciences Centre; Oncology
  • Quebec
    • Laval, Quebec, Canada, H7M 3L9
      • Cite de La Sante de Laval; Hemato-Oncologie
    • Rimouski, Quebec, Canada, G5L 5T1
      • Centre De Sante Et De Services Sociaux Rimouski Neigette
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Hospitalier Universitaire de Sherbrooke
    • Trois-Rivieres, Quebec, Canada, G8Z 3R9
      • Centre Hospitalier Regional de Trois-Rivieres
• Colombia
  • Bogota, Colombia
    • Fundacion Cardioinfantil
  • Cali, Colombia
    • Centro Médico Imbanaco
  • Medellin-Antioquia, Colombia
    • Hospital Pablo Tobon Uribe
  • Pereira, Colombia, 600004
    • Oncólogos de Occidente
• Croatia
  • Rijeka, Croatia, 51000
    • UHC Rijeka
  • Zagreb, Croatia, 10000
    • University Hospital Center Zagreb; Haematology Department
• Denmark
  • Herlev, Denmark, 2730
    • Herlev Uni Hospital; Hæmatologisk Afdeling L 121
  • København Ø, Denmark, 2100
    • Rigshospitalet; Hæmatologisk Klinik
  • Odense C, Denmark, 5000
    • Odense Universitetshospital; Hæmatologisk Afdeling
  • Roskilde, Denmark, 4000
    • Sygehus Syd Roskilde; Onkologisk/haematologisk ambulatorium
  • Vejle, Denmark, 7100
    • Vejle Hospital; Dept of Medicine, Division of Hematology
  • Århus, Denmark, 8000
    • Aarhus Universitetshospital, Hæmatologisk Afdeling R
• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Central Hospital; Dept of Oncology
• France
  • Bordeaux, France, 33077
    • Polyclinique Bordeaux Nord Aquitaine; Chimiotherapie Radiotherapie
  • Creteil, France, 94010
    • Hopital Henri Mondor; Hematologie Clinique
  • Dijon, France, 21079
    • Chu Site Du Bocage;Hematologie Clinique
  • Le Mans, France, 72015
    • Clinique Victor Hugo; Chimiotherapie
  • Marseille, France, 13273
    • Institut J Paolii Calmettes; Onco Hematologie 1
  • Montpellier, France, 34295
    • Hopital Saint Eloi; Hematologie Oncologie Medicale
  • Nantes, France, 44093
    • Hopital Hotel Dieu Et Hme;Hopital De Jour
  • Paris, France, 75475
    • Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)
  • Pessac, France, 33604
    • Hopital De Haut Leveque; Hematologie Clinique
  • Pierre Benite, France, 69495
    • Ch Lyon Sud; Hemato Secteur Jules Courmont
  • Poitiers, France, 86021
    • Hopital De La Miletrie; Hematologie Et Oncologie Medicale
  • Tours, France, 37044
    • Hopital Bretonneau; Hematologie Therapie Cellulaire
• Georgia
  • Tbilisi, Georgia, 0186
    • Chemotherapy and Immunotherapy Clinic Medulla
  • Tbilisi, Georgia, 0177
    • Institute of Hematology and Transfusiology
  • Tbilisi, Georgia, 0112
    • M.Zodelava's Hematology Center
  • Tbilisi, Georgia, 0160
    • Mediclub
• Germany
  • Berlin, Germany, 10707
    • Onkologische Schwerpunktpraxis Kurfürstendamm
  • Darmstadt, Germany, 64283
    • Klinikum Darmstadt GmbH; Med. Klinik V; Onkologie & Hämatologie
  • Dresden, Germany, 01307
    • Gemeinschaftspraxis Dr. med. J. Mohm und Dr. med. G. Prange-Krex; Fachaerzte fuer Innere Medizin
  • Frechen, Germany, 50226
    • PIOH PD Dr. R. Schnell - Dr. H. Schulz - Dr. M. Hellmann
  • Giessen, Germany, 35392
    • Universitätsklinikum Gießen und Marburg GmbH Standort Gießen Medizinische Klinik I
  • Greifswald, Germany, 17475
    • Universitätsklinikum Greifswald Klinik für Innere Medizin C und Poliklinik
  • Halle, Germany, 06110
    • Internistisch-Onkologische Gemeinschaftspraxis; Dres. Rohrberg, Hurtz, Schma usw.
  • Hannover, Germany, 30625
    • Medizinische Hochschule; Zentrum Innere Medizin; Abt. Hämatologie u. Onkologie
  • Karlsruhe, Germany, 76137
    • St. Vincentius Kliniken Ag; Medizinische Klinik Abt. 2
  • Kiel, Germany, 24105
    • UKSH Klinik für Innere Medizin II, Hämatologie und Internistische Onkologie
  • Koeln, Germany, 50674
    • Gemeinschaftspraxis PD Dr. med. Marcel Reiser und Dr. med. Ildiko Kátay
  • Magdeburg, Germany, 39104
    • Onkologische Gemeinschaftspraxis
  • Marburg, Germany, 35037
    • Gemeinschaftspraxis Fr. Dr. med. Balser & Hr. Dr. med. Weidenbach
  • München, Germany, 80335
    • Medizinisches Versorgungszentrum MOP
  • Naunhof, Germany, 04683
    • Praxis Dr.med. Jens Uhlig
  • Olpe, Germany, 57462
    • Praxis Dr. Clemens Müller-Naendrup (Onkologische Schwerpunktpraxis im MVZ 2 GmbH)
  • Recklinghausen, Germany, 45659
    • Prosper-Hospital, Medizinische Klinik I
  • Saalfeld, Germany, 07318
    • Praxis Dr. Fenchel
  • Saarbruecken, Germany, 66113
    • Praxis für Hämatologie & Onkologie
  • Saarbruecken, Germany, 66113
    • Caritas Kilinik St. Theresia; Abt. Innere Medizin
• Greece
  • Athens, Greece, 124 62
    • Attiko Hospital; Haematology Clinic
  • Athens, Greece, 115 27
    • Laiko General Hospital of Athens; A Propedeutical Clinic of Internal Medicine
• Italy
  • Basilicata
    • Potenza, Basilicata, Italy, 85100
      • Azienda Ospedaliera Ospedale S.Carlo; Ematologia
  • Campania
    • Napoli, Campania, Italy, 80131
      • A.O. Universitaria Federico II Di Napoli; Oncologia Ed Endocrinologia Clinica
  • Emilia-Romagna
    • Reggio Emilia, Emilia-Romagna, Italy, 42100
      • AUSL - IRCCS Santa Maria Nuova; U.O. Day Hospital di Oncologia
  • Lazio
    • Roma, Lazio, Italy, 00144
      • Ospedale S. Eugenio; Divisione Di Ematologia
  • Liguria
    • Genova, Liguria, Italy, 16132
      • Uni Degli Studi Di Genova; 1A Divisione Di Ematologia
  • Lombardia
    • Brescia, Lombardia, Italy, 25123
      • A.O. Spedali Civili Di Brescia-P.O. Spedali Civili;U.O. Ematologia
    • Milano, Lombardia, Italy, 20141
      • Irccs Istituto Europeo Di Oncologia (IEO); Emato-Oncologia
  • Puglia
    • San Giovanni Rotondo, Puglia, Italy, 71013
      • IRCCS Ospedale Casa Sollievo Della Sofferenza; Ematologia E Trapianto Di Midollo Osseo
  • Veneto
    • Treviso, Veneto, Italy, 31100
      • Ospedale Ca Foncello; Ematologia
    • Vicenza, Veneto, Italy, 36100
      • Ospedale Di Vicenza; Nefrologia, Ematologia
• Macedonia, The Former Yugoslav Republic of
  • Skopje, Macedonia, The Former Yugoslav Republic of, 1000
    • University Clinic for Hematology; HSCT Department
  • Skopje, Macedonia, The Former Yugoslav Republic of, 1000
    • University Clinic of Hematology Skopje, Hospital Care Department
• Malaysia
  • Ampang, Malaysia, 68000
    • Ampang Hospital; Department of Haematology
  • Sarawak, Malaysia, 93586
    • Sarawak General Hospital; Department of Radiotherapy, Oncology and Palliative care
  • FED. Territory OF Kuala Lumpur
    • Kuala Lumpur, FED. Territory OF Kuala Lumpur, Malaysia, 59100
      • University Malaya Medical Center; Hematology Unit of Department of Internal Medicine
• Mexico
  • Chihuahua, Mexico, 31000
    • Centro Estatal De Cancerologia De Chihuahua; Servicio De Hematologia Banco De Sangre
  • Culiacan, Mexico, 80230
    • Hospital General De Culiacan; Servicio De Hematologia
  • Monterrey, Mexico, 64460
    • Hospital Universitario Dr. Jose E. Gonzalez; Haematology
  • Queretaro, Mexico, 76000
    • Centro de Estudios Clínicos de Querétaro (CECLIQ)
• New Zealand
  • Christchurch, New Zealand, 8011
    • Canterbury Health Laboratories; Haematology
  • Palmerston North, New Zealand, 4442
    • Palmerston North Hospital; Regional Cancer Treatment Service
• Peru
  • Lima, Peru, 18
    • Instituto;Oncologico Miraflores
  • Lima, Peru, 41
    • Oncosalud Sac; Oncología
  • Lima, Peru, Lima 29
    • Hospital Maria Auxiliadora
• Romania
  • Brasov, Romania, 500326
    • Spitalul Clinic Judetean de Urgenta Brasov,Clinica de Hematologie
  • Bucharest, Romania, 022328
    • Fundeni Clinical Inst. ; Hematology Dept
  • Iasi, Romania, 700111
    • Spitalul Clinic Judetean de Urgenta Sf. Spiridon Iasi, Clinica de Hematologie
  • Iasi, Romania, 700483
    • Institutul Regional de Oncologie Iasi; Clinica de Hematologie
  • Targu-mures, Romania, 540136
    • Spitalul Clinic Judetean de Urgenta Targu-Mures; compartiment Hematologie
  • Timisoara, Romania, 300079
    • Spitalul Clinic municipal de Urgenta Timisoara; Clinica de Hematologie
• Russian Federation
  • Kazan, Russian Federation, 420029
    • Clinical Oncology Dispensary of Ministry of Health of Tatarstan
  • Moscow, Russian Federation, 115478
    • N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis
  • Moscow, Russian Federation, 125167
    • Haematology Research Center; Haematology
  • Penza, Russian Federation, 440071
    • Penza Regional Oncology Dispensary
  • Saint-Petersburg, Russian Federation, 197022
    • St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta
  • St Petersburg, Russian Federation, 191024
    • Research Inst. of Hematology & Blood Transfusion ; Hematology
  • St.Petersburg, Pesochny, Russian Federation, 197758
    • Russian Scientific Center of Radiology and Surgical Technologies; Dept of Radiology
• Serbia
  • Belgrade, Serbia, 11000
    • Institute of Hematology
  • Novi Sad, Serbia, 21000
    • Clinical Center Vojvodine; Clinic for Hematology
• Singapore
  • Singapore, Singapore, 119228
    • National University Hospital; National University Cancer Institute, Singapore (NCIS)
  • Singapore, Singapore, 169610
    • National Cancer Centre; Medical Oncology
  • Singapore, Singapore, 169608
    • Singapore General Hospital; Department of Haematology
• Slovakia
  • Bratislava, Slovakia, 812 50
    • St. Elisabeths Cancer Center
  • Bratislava, Slovakia, 833 10
    • National Cancer Inst. ; Dept. of Chemotherapy
• South Africa
  • Bloemfontein, South Africa, 9301
    • National Hospital; Oncotherapy Dept
  • Congella, South Africa, 4013
    • King Edward VIII; Department of Haematology
  • Durban, South Africa, 4091
    • Durban Oncology Center
  • Johannesburg, South Africa, 2193
    • University of Witwatersrand/Johannesburg Hospital; Dept. of ocnology
  • Kraaifontein, South Africa, 7570
    • Cancercare
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron; Servicio de Hematologia
  • Barcelona, Spain, 08036
    • Hospital Clínic i Provincial; Servicio de Hematología y Oncología
  • Barcelona, Spain, 08003
    • Hospital del Mar; Servicio de Hematologia
  • Barcelona, Spain, 08907
    • Hospital Duran i Reynals; Servicio de Hematologia
  • Madrid, Spain, 28006
    • Hospital Universitario de la Princesa; Servicio de Hematologia
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal; Servicio de Hematologia
  • Murcia, Spain, 30120
    • Hospital Universitario Virgen de Arrixaca; Servicio de Hematologia
  • Salamanca, Spain, 37007
    • Hospital Clinico Universitario de Salamanca;Servicio de Hematologia
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio; Servicio de Hematologia
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe; Servicio de Oncologia
  • Cadiz
    • Cádiz, Cadiz, Spain, 11009
      • Hospital Universitario Puerta del Mar; Servicio de Hematologia
• Thailand
  • Bangkok, Thailand, 10400
    • National Cancer Inst.
  • Bangkok, Thailand, 10700
    • Siriraj Hospital; Division of Hematology, Department of Medicine
  • Khon Kaen, Thailand, 40002
    • Srinagarind Hospital, Khon Kaen Uni ; Dept of Medicine
• Turkey
  • Adana, Turkey, 01120
    • Adana Baskent University Hospital; Medical Oncology
  • Istanbul, Turkey, 34098
    • Istanbul University Cerrahpasa Medical Faculty; Hematology Department
  • Istanbul, Turkey, 34394
    • Bilim University School of Medicine; Hematology
  • Izmir, Turkey, 35100
    • Ege Uni Medical School; Hematology
  • Izmir, Turkey, 35100
    • Dokuz Eylul Uni ; Hematology
• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Ninewells Hospital & Medical School; Ward 34
  • Maidstone, United Kingdom, ME16 9QQ
    • Maidstone & Tonbridge Wells Hospital; Kent Oncology Center
  • Plymouth, United Kingdom, PL6 8DH
    • Derriford Hospital; Department of Haematology
  • Romford, United Kingdom, RM7 0AG
    • Queen's Hospital; Oncology
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital
  • Wakefield, United Kingdom, WF1 4DG
    • Pinderfields General Hospital; Dept of Haematology
  • Wolverhampton, United Kingdom, WV10 0QP
    • New Cross Hospital; Dept. Of Haematology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Cluster of differentiation 20 (CD20)-positive, follicular Non-Hodgkin's lymphoma grade 1, 2, 3a. A tumor biopsy must have been performed within 6 months before study entry with material available for central review
• No prior treatment
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Exclusion Criteria:

• Grade 3b follicular lymphoma
• Transformation to high-grade lymphoma secondary to follicular lymphoma
• Types of Non-Hodgkin's lymphoma other than follicular lymphoma
• Presence or history of central nervous system (CNS) disease
• Corticoid therapy during the last 4 weeks, except prednisone treatment less than (<) 20 milligrams per day (mg per day)
• Known active bacterial, viral, fungal, or mycobacterial, or any major episode of infections requiring hospitalization or treatment with IV antibiotics within 4 weeks of start of study medication, or oral antibiotics within 2 weeks prior to start of study medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP); Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) or cyclophosphamide, vincristine, prednisolone (CVP) chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.	Drug: Rituximab IV; Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.; Other Names: MabThera; Drug: Cyclophosphamide; Eight cycles of cyclophosphamide (750 mg/m^2 IV) administered every 3 weeks.; Drug: Doxorubicin; Eight cycles of doxorubicin (50 mg/m^2 IV) administered every 3 weeks.; Drug: Vincristine; Eight cycles of doxorubicin (1.4 mg/m^2 IV) administered every 3 weeks.; Drug: Prednisone/Prednisolone; Eight cycles of prednisone/prednisolone (100 mg/day or 40 mg/m^2/day IV/orally) administered Days 1 to 5 of every 21 days cycle.
EXPERIMENTAL: Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP); First cycle of rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.	Drug: Cyclophosphamide; Eight cycles of cyclophosphamide (750 mg/m^2 IV) administered every 3 weeks.; Drug: Doxorubicin; Eight cycles of doxorubicin (50 mg/m^2 IV) administered every 3 weeks.; Drug: Vincristine; Eight cycles of doxorubicin (1.4 mg/m^2 IV) administered every 3 weeks.; Drug: Prednisone/Prednisolone; Eight cycles of prednisone/prednisolone (100 mg/day or 40 mg/m^2/day IV/orally) administered Days 1 to 5 of every 21 days cycle.; Drug: Rituximab SC; First cycle of rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.; Other Names: MabThera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab		Stage I: Cycle (Cy) 7 Day (D) 21 (within 2 hours predose on Cy8) of induction treatment (1 Cy=3 weeks)
Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for Non-Hodgkin Lymphoma (NHL)	Overall Response comprised complete response (CR), CR unconfirmed (CRu), or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and computed tomography (CT) scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by more than (>) 75% in the sum of the products of greatest diameters (SPD); PR: Greater than or equal to (≥) 50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.	Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Overall Response comprised CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in the SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.	Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Overall Response comprised of CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumour response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.	Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Complete Response was comprised CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.	Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.	Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL	Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.	Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL	Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.	Stage I and II: Baseline up to 57 days after last maintenance dose (last maintenance dose: maintenance Cy12/Study Cy20 [30 months]) (up to data cutoff of 31 Oct 2017 [up to 6 years]) (1 Cy=8 weeks)
Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL	Overall Response comprised of CR, CRu, or PR . A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.	Stage I and II: Baseline up to 57 days after last maintenance dose (last maintenance dose: maintenance Cy12/Study Cy20 [30 months]) (up to data cutoff of 31 Oct 2017 [up to 6 years]) (1 Cy=8 weeks)
Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death	Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node >1 cm in its short axis or in the SPD of more than one node. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)
Stage I and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL	PFS was defined as the time from randomization to disease progression/relapse or death due to any cause. If the specified event (disease progression/relapse, death) did not occur, PFS was censored at the last tumor assessment date showing no disease progression, either during treatment or follow-up. Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node >1 cm in its short axis or in the SPD of more than one node. PFS analysis was performed using Kaplan - Meier curves. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)
Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse, New Anti-Lymphoma Treatment or Death Assessed Using International Working Group Response Criteria for NHL	Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node >1 cm in its short axis or in the SPD of more than one node. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)
Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL	Event-free survival was defined as the time from randomization to disease progression/relapse, death or initiation of new NHL therapy. If the specified event (progression/relapse, death or new anti-lymphoma treatment) did not occur, event-free survival was censored at the last tumor assessment date either during treatment or follow up. Event-free survival analysis was performed using Kaplan-Meier curves. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])	Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)
Percentage of Participants Who Died		Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])
Overall Survival (OS)	OS was defined as the time from randomization to death due to any cause. Participants without event were censored at the time of last follow-up information for survival, ie, at the last time known to be alive.	Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])
Stage I: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab	AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Predose (within 2 hr) and 24 hrs postdose on Cy 7 (D1,3,7,15), predose (0 hr) on Cy 8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy 7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 [up to 26 months])	Stage I (Induction): Predose (within 2 hour [hr]) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)
Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab	Predose (within 2 hr) and 24 hrs postdose on Cy7 (D1,3,7,15), predose (0 hr) on Cy8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 [up to 26 months])	Stage I (Induction): Predose (within 2hr) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)
Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle	Stage I and II (Induction): Rituximab IV: Predose (within 2 hr) on D1 of Cy1-8 (1 Cy=3 weeks & 4 weeks for Cy8); Rituximab SC: Predose (within 2 hr) on D1 of Cy1 & Cy3-8 (1 Cy=3 weeks and 4 weeks for Cy8), predose (within 2 hr) on D0 of Cy2 (up to data cutoff of 31 Oct 2013 [up to 32 months])	Stage I and II (Pooled): Predose (within 2hr) up to data cutoff of 31 Oct 2013 [up to 32 months]) (See detailed timeframe in Outcome Measure description)
Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle	Stage I and II (maintenance): D29 of Cy8 (induction; 1 Cy=4 weeks), predose (within 2 hr) on D1 of Cy9 to 19 (maintenance Cy1 to 12 [1 Cy=8 weeks]; up to data cutoff of 11 Jan 2016 [up to 6 years])	Stage I and II (maintenance): Predose (within 2hr) up to data cutoff of 11 Jan 2016 [up to 6 years]) (See detailed timeframe in Outcome Measure description)
Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration		12 weeks, 24 weeks, and 36 weeks after the last rituximab administration (up to data cutoff of 11 Jan 2016 [up to 6 years])
Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase	Depletion is defined as a cluster of differentiation (CD) 19 value <80 cells per cubic millimeter (cells/mm^3).	Stage I and II (induction): for rituximab IV - D1 of Cy 1 to 8 (1 Cy=3 weeks); for rituximab SC - D1 of Cy 1 and Cy 3 to 8, D0 of Cy 2
Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase	Depletion is defined as a CD19 value <80 cells/mm^3.	Stage I and II (maintenance): D1 of Cy 9 to 20 (1 Cy=8 weeks) (up to data cutoff of 11 Jan 2016 [up to 6 years])
Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab	Levels of HACA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 [up to 6 years])	Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)
Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab	Levels of HAHA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 [up to 6 years])	Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)
Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20	All investigator physicians and nurses involved in this study were asked to provide the staff time that could be saved with each administration of rituximab SC as compared with rituximab IV to participants in routine practice afetr Cy 8, 15, 20 and categorized as less than (<) 1 hr, at least 1 hr but <2 hrs, at least 2 hrs but <3 hrs, at least 3 hrs but <4 hrs, >/=4 hrs. Staff were asked not to consider the time needed for the first IV administration. Analysis was done in all participants to show a comparison on the time saved by staffs when administered via SC and IV.	After Cycle 8 of induction treatment (24 weeks) and during the maintenance part of the study after 12 months (i.e., Cycle 15), and after the end of the maintenance treatment, (i.e., Cycle 20) (1 Cycle=4 weeks for Cycle 8 and 8 weeks for Cycles 15 and 20)
Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion	All investigator physicians and nurses involved in this study were asked to complete question i.e. "Which formulation of rituximab (SC or IV) do you think is more convenient?" based on their experience with the rituximab SC and IV formulations across all participants and presented as rituximab SC is much more convenient; rituximab SC is a little more convenient; both formulations are equally convenient; rituximab IV is a little more convenient; and rituximab IV is much more convenient.	After Cycle 8 of induction treatment (24 weeks) and during the maintenance part of the study after 12 months (i.e., Cycle 15), and after the end of the maintenance treatment, (i.e., Cycle 20) (1 Cycle=4 weeks for Cycle 8 and 8 weeks for Cycles 15 and 20)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Davies A, Merli F, Mihaljevic B, Mercadal S, Siritanaratkul N, Solal-Celigny P, Boehnke A, Berge C, Genevray M, Zharkov A, Dixon M, Brewster M, Barrett M, MacDonald D. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017 Jun;4(6):e272-e282. doi: 10.1016/S2352-3026(17)30078-9. Epub 2017 May 2.
• Davies A, Merli F, Mihaljevic B, Siritanaratkul N, Solal-Celigny P, Barrett M, Berge C, Bittner B, Boehnke A, McIntyre C, Macdonald D. Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol. 2014 Mar;15(3):343-52. doi: 10.1016/S1470-2045(14)70005-1. Epub 2014 Feb 10.
• Mao CP, Brovarney MR, Dabbagh K, Birnbock HF, Richter WF, Del Nagro CJ. Subcutaneous versus intravenous administration of rituximab: pharmacokinetics, CD20 target coverage and B-cell depletion in cynomolgus monkeys. PLoS One. 2013 Nov 12;8(11):e80533. doi: 10.1371/journal.pone.0080533. eCollection 2013.
• Shpilberg O, Jackisch C. Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase. Br J Cancer. 2013 Sep 17;109(6):1556-61. doi: 10.1038/bjc.2013.371. Epub 2013 Sep 3.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 15, 2011
• Primary Completion (ACTUAL): June 12, 2012
• Study Completion (ACTUAL): October 31, 2017

Study Registration Dates

• First Submitted: September 10, 2010
• First Submitted That Met QC Criteria: September 13, 2010
• First Posted (ESTIMATE): September 14, 2010

Study Record Updates

• Last Update Posted (ACTUAL): November 27, 2018
• Last Update Submitted That Met QC Criteria: October 29, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Prednisolone; Cyclophosphamide; Rituximab; Prednisone; Doxorubicin; Vincristine
• Other Study ID Numbers: BO22334; 2010-021377-36