A Study to Compare Subcutaneous Versus Intravenous MabThera (Rituximab) in Combination With Chemotherapy in Patients With Chronic Lymphocytic Leukemia

NCT01292603 | Completed Phase 1 Results

• 2 other identifiers: BO253412010-021380-32
• Study Type: interventional
• Target: 240
• Locations: 19 countries
• Sites: 84

Brief Summary

This randomized, parallel-group, multi-center study will compare the pharmacokinetics and safety of subcutaneous administration of MabThera (rituximab) versus intravenous MabThera in combination with chemotherapy in previously untreated patients with chronic lymphocytic leukemia (CLL). The study consists of 2 parts. In part 1, patients who have previously received 4 cycles of intravenous MabThera will receive in Cycle 5 intravenous MabThera and in Cycle 6 subcutaneous MabThera. In part 2, patients will be randomized to receive either 6 cycles of intravenous MabThera, or 1 cycle of intravenous MabThera and 5 cycles of subcutaneous MabThera. Additionally, all patients will receive chemotherapy (fludarabine and cyclophosphamide) on Days 1-3 or Days 1-5 of every cycle. The anticipated time on study drug is 24 weeks.

Conditions

Lymphocytic Leukemia, Chronic

Outcome Measures

Primary Outcomes (2)

• Part 1: Subcutaneous Rituximab Dose Resulting in Trough Concentration (Ctrough) Levels Non-Inferior to Intravenous Rituximab

  Ctrough is defined as the trough or minimum serum concentration. Pharmacokinetic parameters for rituximab were assessed during Cycles 5 (IV rituximab) and 6 (SC rituximab). Rituximab pharmacokinetic (PK) data from Part 1 were integrated into a population PK model using parametric, nonlinear, mixed-effects modelling. Rituximab IV 500 mg/m\^2 administered once every 4 weeks was compared to fixed doses of rituximab SC between 1400 mg and 1870 mg. The dose selection was performed on Ctrough concentrations at Cycle 5 (pre-dose Cycle 6). A test of the probability of success was applied to each of the 100 replicates, and the percentage of replicates with a positive test corresponded to the probability of success of the trial.

  Pre-dose and post-dose (15 minutes to end of infusion) on Day 1 and on Days 2, 5, 11 and 15 of Cycle 5 and Pre-dose, Post-dose on Days 2, 3, 5,11, 15 and 29 of Cycle 6; Pre-dose was taken 2 hours prior rituximab dose

• Part 2: Rituximab C Trough Levels at Cycle 5

  Ctrough is defined as the trough or minimum serum concentration in a given cycle of treatment. The objective of Part 2 was to demonstrate the comparability of the observed Ctrough of rituximab SC 1600 mg and rituximab IV 500 mg/m2 at Cycle 5, as assessed by a non-inferiority test with a lower boundary of at least 0.8 for the 90% CI.

  +/- 25hours around the 28th day post the 5th Cycle of Rituximab administration

Secondary Outcomes (13)

• Part 2: Observed Area Under the Serum Concentration-Curve (AUC) of Rituximab at Cycle 6

  Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6

• Part 2: Maximum Observed Concentration (Cmax) of Rituximab at Cycle 6

  Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6

• Part 2: Time to Cmax (Tmax) of Rituximab at Cycle 6

  Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6

• Part 2: Terminal Half-Life of Rituximab at Cycle 6

  Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6

• Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration

  Days 4 to 5 in Cycle 6

Study Arms (3)

1

EXPERIMENTAL

Drug: Cyclophosphamide; Drug: Fludarabine; Drug: rituximab [MabThera]

2

EXPERIMENTAL

Drug: Cyclophosphamide; Drug: Fludarabine; Drug: rituximab [MabThera]

3

EXPERIMENTAL

Drug: Cyclophosphamide; Drug: Fludarabine; Drug: rituximab [MabThera]

Interventions

Cyclophosphamide DRUG

Days 1-3 or Days 1-5 of cycles 1-6

1; 2; 3

Fludarabine DRUG

Days 1-3 or Days 1-5 of cycles 1-6

1; 2; 3

rituximab [MabThera] DRUG

One cycle of intravenous MabThera, followed by 5 cycles of subcutaneous MabThera

3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients, \>/=18 years of age
• Patients with treatment-requiring chronic lymphocytic leukemia (CLL)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Life expectancy \>6 months

You may not qualify if:

• Transformation to aggressive B-cell malignancy
• History of other malignancy unless the patient was treated with curative intent and has been in remission for more than 5 years prior to enrolment
• HIV or Hepatitis B positive unless clearly due to vaccination
• Inadequate liver or renal function
• Any coexisting medical or psychological condition that would preclude participation in the required study procedures
• Any previous treatment for CLL except for up to 4 cycles of rituximab IV in combination with FC chemotherapy as first-line treatment for CLL
• Any previous treatment for CLL

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (84)

Fundaleu; Haematology

Buenos Aires, C1114AAN, Argentina

Location

Cemic; Haematology

Buenos Aires, C1431FWO, Argentina

Location

HOSPITAL PRIVADO - CENTRO MEDICO DE CÓRDOBA; Dpto Oncología

Córdoba, 5016, Argentina

Location

St George Hospital; Department of Haematology

Kogarah, New South Wales, 2217, Australia

Location

Royal Brisbane and Women'S Hospital; Haematology

Herston, Queensland, 4029, Australia

Location

Ashford Cancer Center Research

Kurralta Park, South Australia, 5037, Australia

Location

Queen Elizabeth Hospital; Haematology

Woodville South, South Australia, 5011, Australia

Location

St Vincent'S Hospital; Haematology

Fitzroy, Victoria, 3065, Australia

Location

Frankston Hospital; Oncology/Haematology

Frankston, Victoria, 3199, Australia

Location

Hospital da Cidade de Passo Fundo; Centro de Pesquisa em Oncologia

Passo Fundo, Rio Grande do Sul, 99010-260, Brazil

Location

Hospital Mae de Deus

Porto Alegre, Rio Grande do Sul, 90470-340, Brazil

Location

Hospital Sirio Libanes; Centro de Oncologia

São Paulo, São Paulo, 01308-050, Brazil

Location

Hospital das Clinicas - FMUSP

São Paulo, São Paulo, 05403-000, Brazil

Location

Queen Elizabeth II Health Sciences Centre; Oncology

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology

Montreal, Quebec, H3T 1E2, Canada

Location

Centre de sante et de services sociaux Rimouski Neigette

Rimouski, Quebec, G5L 5T1, Canada

Location

Centre Hospitalier Universitaire de Sherbrooke

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Instituto Nacional del Cancer

Santiago, 8380000, Chile

Location

Centro Internacional de Estudios Clínicos (CIEC)

Santiago, 8420383, Chile

Location

Clinical Hospital Merkur; Dept of Haematology

Zagreb, 10000, Croatia

Location

University Hospital Center Zagreb; Haematology Department

Zagreb, 10000, Croatia

Location

Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika

Brno, 625 00, Czechia

Location

University Hospital and Medical School; IV.Dept. of Internal Medicine and Hematology

Hradec Králové, 500 05, Czechia

Location

Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK

Prague, 128 08, Czechia

Location

Centre Francois Baclesse

Caen, 14076, France

Location

Institut J Paolii Calmettes; Onco Hematologie 1

Marseille, 13273, France

Location

Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)

Paris, 75475, France

Location

Hopital Robert Debre; Hematologie Clinique

Reims, 51092, France

Location

Hopitaux De Brabois; Hematologie Medecine Interne

Vandœuvre-lès-Nancy, 54511, France

Location

Onkologische Schwerpunktpraxis Kurfürstendamm

Berlin, 10707, Germany

Location

Onkologischer Schwerpunkt am Oskar-Helene-Heim; Dres. Herrenberger, Keitel-Wittig u. Kirsch

Berlin, 14195, Germany

Location

Klinik der Uni zu Köln; Klinik für Innere Medizin

Cologne, 50924, Germany

Location

BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie

Dresden, 01307, Germany

Location

Klinikum Frankfurt; Medizinische Klinik I

Frankfurt (Oder), 15236, Germany

Location

Universitätsklinikum Greifswald Klinik für Innere Medizin C und Poliklinik

Greifswald, 17475, Germany

Location

Onkologische Schwerpunktpraxis Dres. Bernd Gaede, Hans-Ulrich Ehlers, Ulrike Rodewig u.w.

Hanover, 30171, Germany

Location

Gemeinschaftspraxis Dr. Siehl & Dr. Soeling

Kassel, 34119, Germany

Location

K&K Studien GbR

Landshut, 84028, Germany

Location

Onkologische Schwerpunktpraxis Lübeck

Lübeck, 23562, Germany

Location

Gemeinschaftspraxis Fr. Dr. med. Balser & Hr. Dr. med. Weidenbach

Marburg, 35037, Germany

Location

Medizinisches Versorgungszentrum MOP

München, 80335, Germany

Location

Klinikum Grosshadern der LMU

München, 81377, Germany

Location

Gemeinschaftspraxis Dr. med. Holger Klaproth / Dr. med. Anca Astrid Cura

Neunkirchen/Saar, 66538, Germany

Location

Prosper-Hospital, Medizinische Klinik I

Recklinghausen, 45659, Germany

Location

Laiko General Hospital of Athens; A Propedeutical Clinic of Internal Medicine

Athens, 115 27, Greece

Location

Papageorgiou General Hospital of Thessaloniki; Hematology Clinic

Thessaloniki, 54629, Greece

Location

IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica

Meldola, Emilia-Romagna, 47014, Italy

Location

Az. Osp. S. Maria Delle Croci; U.O. Di Ematologia

Ravenna, Emilia-Romagna, 48100, Italy

Location

Ospedale Infermi Di Rimini; Unità Operativa di Oncologia e Oncoematologia

Rimini, Emilia-Romagna, 47900, Italy

Location

A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica

Udine, Friuli Venezia Giulia, 33100, Italy

Location

Istituto S. Raffaele Monte Tabor; Divisione Ematologia E Utmo

Milan, Lombardy, 20132, Italy

Location

ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA; Struttura Complessa di Ematologia

Milan, Lombardy, 20162, Italy

Location

Univ. Piemonte Est Amedeo Avogadro; Div.Ematologia- Dip.Clinica Med.Sperim.& Ircad

Novara, Piedmont, 28100, Italy

Location

Policlinico G. B. Rossi; Divisione Di Ematologia

Verona, Veneto, 37134, Italy

Location

Centro Estatal De Cancerologia De Chihuahua; Servicio De Hematologia Banco De Sangre

Chihuahua City, 31000, Mexico

Location

Hospital General De Culiacan; Servicio De Hematologia

Culiacán, 80230, Mexico

Location

Hospital Universitario Dr. Jose E. Gonzalez; Haematology

Monterrey, 64460, Mexico

Location

Canterbury Health Laboratories; Haematology

Christchurch, 8011, New Zealand

Location

Wellington Hospital; Wellington Blood and Cancer Centre

Newtown, 6021, New Zealand

Location

Uniwersyteckie Centrum Kliniczne; Klinika Hematologii i Transplantologii

Gdansk, 80-952, Poland

Location

Katedra i Klinika Hematoonkologii i Transplantacji Szpiku; Uniwersytetu Medycznego w Lublinie

Lublin, 20-081, Poland

Location

Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Lymphoma Dept.

Warsaw, 02-781, Poland

Location

Medical Uni of Wroclaw; Hematology

Wroclaw, 50-367, Poland

Location

Hospital de Santa Maria; Servico de Hematologia e Transplantacao de Medula

Lisbon, 1600, Portugal

Location

IPO do Porto; Servico de Onco-Hematologia

Porto, 4200-072, Portugal

Location

N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis

Moscow, 115478, Russia

Location

City Clinical Hospital After Botkin; Hematology

Moscow, 125101, Russia

Location

Haematology Research Center; Haematology

Moscow, 125167, Russia

Location

Penza Regional Oncology Dispensary

Penza, 440071, Russia

Location

Clinical MSCh No1

Perm, 614077, Russia

Location

St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta

Saint Petersburg, 197022, Russia

Location

National Oncology Inst. ; Dept. of Haematology

Bratislava, 833 10, Slovakia

Location

University Hospital; Clinic of Hematology & Transfusiology

Bratislava, 851 07, Slovakia

Location

Hospital Universitari Vall d'Hebron; Servicio de Hematologia

Barcelona, 08035, Spain

Location

Hospital Universitario de la Princesa; Servicio de Hematologia

Madrid, 28006, Spain

Location

Hospital Universitario Puerta de Hierro; Servicio de Hematologia

Madrid, 28222, Spain

Location

Hospital Clinico Universitario de Salamanca;Servicio de Hematologia

Salamanca, 37007, Spain

Location

Hospital Universitario Virgen del Rocio; Servicio de Hematologia

Seville, 41013, Spain

Location

Complejo Hospitalario de Toledo- H. Virgen de la Salud; Servicio de Hematología

Toledo, 45004, Spain

Location

Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia

Valencia, 46010, Spain

Location

Hacettepe Uni Medical Faculty; Hematology

Ankara, 06100, Turkey (Türkiye)

Location

Istanbul University Cerrahpasa Medical Faculty; Hematology Department

Istanbul, 34098, Turkey (Türkiye)

Location

Dokuz Eylul Uni ; Hematology

Izmir, 35100, Turkey (Türkiye)

Location

Ege University ARGEFAR

Izmir, 35100, Turkey (Türkiye)

Location

Related Publications (4)

• Assouline S, Buccheri V, Delmer A, Gaidano G, Trneny M, Berthillon N, Brewster M, Catalani O, Li S, McIntyre C, Sayyed P, Badoux X. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016 Mar;3(3):e128-38. doi: 10.1016/S2352-3026(16)00004-1.

  PMID: 26947201 DERIVED

• Assouline S, Buccheri V, Delmer A, Gaidano G, McIntyre C, Brewster M, Catalani O, Hourcade-Potelleret F, Sayyed P, Badoux X. Pharmacokinetics and safety of subcutaneous rituximab plus fludarabine and cyclophosphamide for patients with chronic lymphocytic leukaemia. Br J Clin Pharmacol. 2015 Nov;80(5):1001-9. doi: 10.1111/bcp.12662. Epub 2015 Jul 29.

  PMID: 25900065 DERIVED

• 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.

  PMID: 24265828 DERIVED

• 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.

  PMID: 24002601 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

Cyclophosphamide; fludarabine; Rituximab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann- LaRoche

genentech@druginfo.com

1-800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 8, 2011
• First Posted: February 9, 2011
• Study Start: April 18, 2011
• Primary Completion: May 7, 2014
• Study Completion: November 17, 2017
• Last Updated: December 19, 2018
• Results First Posted: December 15, 2015

Record last verified: 2018-11

Locations

PT (2); CA (4); ME (3); TU (4); AR (3); IT (8); DE (15); CL (2); BR (4); CR (2); NZ (2); CZ (3); ES (7); PL (4); AU (6); GR (2); RU (6); SL (2); FR (5)