Clinical trial NCT01292603: A Study to Compare Subcutaneous Versus Intravenous MabThera (Rituximab) in Combination With Chemotherapy in Patients With Chronic Lymphocytic Leukemia
Official title: An Adaptive, Comparative, Randomized, Parallel-group, Multi Center, Phase Ib Study of Subcutaneous (SC) Rituximab Versus Intravenous (IV) Rituximab Both in Combination With Chemotherapy (Fludarabine and Cyclophosphamide), in Patients With Previously Untreated CLL
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphocytic Leukemia, Chronic
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2011-02-09
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Additional exclusion criterion for Part 1:

* 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

Additional exclusion criterion for Part 2:

* Any previous treatment for CLL

Primary outcomes:
measure: Part 1: Subcutaneous Rituximab Dose Resulting in Trough Concentration (Ctrough) Levels Non-Inferior to Intravenous Rituximab
timeFrame: 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
measure: Part 2: Rituximab C Trough Levels at Cycle 5
timeFrame: +/- 25hours around the 28th day post the 5th Cycle of Rituximab administration
Secondary outcomes:
measure: Part 2: Observed Area Under the Serum Concentration-Curve (AUC) of Rituximab at Cycle 6
timeFrame: 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
measure: Part 2: Maximum Observed Concentration (Cmax) of Rituximab at Cycle 6
timeFrame: 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
measure: Part 2: Time to Cmax (Tmax) of Rituximab at Cycle 6
timeFrame: 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
measure: Part 2: Terminal Half-Life of Rituximab at Cycle 6
timeFrame: 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
measure: Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration
timeFrame: Days 4 to 5 in Cycle 6
measure: Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV
timeFrame: Days 4-5 in Cycle 6
measure: Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV
timeFrame: Days 4-5 in Cycle 6
measure: Part 1: Percentage of Participants With Anti-Rituximab Antibodies
timeFrame: Predose at Cycles 5 and 6 and at each follow up visit until 24 months after the last dose
measure: Part 2: Percentage of Participants With Anti-Rituximab Antibodies
timeFrame: Day 0 of Cycle 1 and Day 1 of Cycles 1, 2, 3, 4, 5, and 6 and at each follow-up visit until 24 months after the last dose of rituximab.
measure: Part 1: Total Cluster Differentiation19 Positive (CD19+) B-Cell Counts by Visit
timeFrame: Day 1 of Cycles 5 and 6 and Follow-up Days 28 and 56 and Follow-up Visits at Months 3, 6, 9, 12, 15,18, 21 and 24
measure: Part 1: Percentage of Participants With Total B-Cell Depletion by Visit
timeFrame: Day 1 pre-dose of Cycles 5 and 6 and Follow-up Days 28 and 56 and Follow-up Visits at Months 3, 6, 9, 12, 15, 18, 21 and 24
measure: Part 2: Total CD19+ B-Cell Counts by Visit
timeFrame: Cycle 1 pre-dose, 60 minutes post-dose, Days 2 and 3 in Cycle 2, day 1 pre-dose in Cycles 3, 4, 5 and 6, Follow-up Days 28 and 56, and Follow-up Visits at Months 3, 6, 9, 12, 15, and 18 and Withdrawal Visit
measure: Part 2: Percentage of Participants With Total B-Cell Depletion by Visit
timeFrame: Cycle 1 Pre-dose, 60 minutes post-dose, Days 2 and 3 in Cycle 2, day 1 in Cycles 3, 4, 5 and 6, Follow-up Days 28 and 56, and Follow-up Visits at Months 3, 6, 9, 12, 15, and 18 and Withdrawal Visit
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: Fundaleu; Haematology
city: Buenos Aires
country: Argentina
facility: Cemic; Haematology
city: Córdoba
country: Argentina
facility: HOSPITAL PRIVADO - CENTRO MEDICO DE CÓRDOBA; Dpto Oncología
city: Kogarah
country: Australia
facility: St George Hospital; Department of Haematology
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women'S Hospital; Haematology
state: Queensland
city: Kurralta Park
country: Australia
facility: Ashford Cancer Center Research
state: South Australia
city: Woodville South
country: Australia
facility: Queen Elizabeth Hospital; Haematology
state: South Australia
city: Fitzroy
country: Australia
facility: St Vincent'S Hospital; Haematology
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital; Oncology/Haematology
state: Victoria
city: Passo Fundo
country: Brazil
facility: Hospital da Cidade de Passo Fundo; Centro de Pesquisa em Oncologia
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital Mae de Deus
state: RS
city: Sao Paulo
country: Brazil
facility: Hospital Sirio Libanes; Centro de Oncologia
state: SP
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP
state: SP
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre; Oncology
state: Nova Scotia
city: Montreal
country: Canada
facility: McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology
state: Quebec
city: Rimouski
country: Canada
facility: Centre de sante et de services sociaux Rimouski Neigette
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
city: Santiago
country: Chile
facility: Instituto Nacional del Cancer
city: Santiago
country: Chile
facility: Centro Internacional de Estudios Clínicos (CIEC)
city: Zagreb
country: Croatia
facility: Clinical Hospital Merkur; Dept of Haematology
city: Zagreb
country: Croatia
facility: University Hospital Center Zagreb; Haematology Department
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika
city: Hradec Kralove
country: Czechia
facility: University Hospital and Medical School; IV.Dept. of Internal Medicine and Hematology
city: Praha 2
country: Czechia
facility: Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK
city: Caen
country: France
facility: Centre Francois Baclesse
city: Marseille
country: France
facility: Institut J Paolii Calmettes; Onco Hematologie 1
city: Paris
country: France
facility: Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)
city: Reims
country: France
facility: Hopital Robert Debre; Hematologie Clinique
city: Vandoeuvre Les Nancy
country: France
facility: Hopitaux De Brabois; Hematologie Medecine Interne
city: Berlin
country: Germany
facility: Onkologische Schwerpunktpraxis Kurfürstendamm
city: Berlin
country: Germany
facility: Onkologischer Schwerpunkt am Oskar-Helene-Heim; Dres. Herrenberger, Keitel-Wittig u. Kirsch
city: Dresden
country: Germany
facility: BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie
city: Frankfurt an der Oder
country: Germany
facility: Klinikum Frankfurt; Medizinische Klinik I
city: Greifswald
country: Germany
facility: Universitätsklinikum Greifswald Klinik für Innere Medizin C und Poliklinik
city: Hannover
country: Germany
facility: Onkologische Schwerpunktpraxis Dres. Bernd Gaede, Hans-Ulrich Ehlers, Ulrike Rodewig u.w.
city: Kassel
country: Germany
facility: Gemeinschaftspraxis Dr. Siehl & Dr. Soeling
city: Köln
country: Germany
facility: Klinik der Uni zu Köln; Klinik für Innere Medizin
city: Landshut
country: Germany
facility: K&K Studien GbR
city: Lübeck
country: Germany
facility: Onkologische Schwerpunktpraxis Lübeck
city: Marburg
country: Germany
facility: Gemeinschaftspraxis Fr. Dr. med. Balser & Hr. Dr. med. Weidenbach
city: Muenchen
country: Germany
facility: Klinikum Grosshadern der LMU
city: München
country: Germany
facility: Medizinisches Versorgungszentrum MOP
city: Neunkirchen/Saar
country: Germany
facility: Gemeinschaftspraxis Dr. med. Holger Klaproth / Dr. med. Anca Astrid Cura
city: Recklinghausen
country: Germany
facility: Prosper-Hospital, Medizinische Klinik I
city: Athens
country: Greece
facility: Laiko General Hospital of Athens; A Propedeutical Clinic of Internal Medicine
city: Thessaloniki
country: Greece
facility: Papageorgiou General Hospital of Thessaloniki; Hematology Clinic
city: Meldola
country: Italy
facility: IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica
state: Emilia-Romagna
city: Ravenna
country: Italy
facility: Az. Osp. S. Maria Delle Croci; U.O. Di Ematologia
state: Emilia-Romagna
city: Rimini
country: Italy
facility: Ospedale Infermi Di Rimini; Unità Operativa di Oncologia e Oncoematologia
state: Emilia-Romagna
city: Udine
country: Italy
facility: A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica
state: Friuli-Venezia Giulia
city: Milano
country: Italy
facility: Istituto S. Raffaele Monte Tabor; Divisione Ematologia E Utmo
state: Lombardia
city: Milano
country: Italy
facility: ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA; Struttura Complessa di Ematologia
state: Lombardia
city: Novara
country: Italy
facility: Univ. Piemonte Est Amedeo Avogadro; Div.Ematologia- Dip.Clinica Med.Sperim.& Ircad
state: Piemonte
city: Verona
country: Italy
facility: Policlinico G. B. Rossi; Divisione Di Ematologia
state: Veneto
city: Chihuahua
country: Mexico
facility: Centro Estatal De Cancerologia De Chihuahua; Servicio De Hematologia Banco De Sangre
city: Culiacan
country: Mexico
facility: Hospital General De Culiacan; Servicio De Hematologia
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. Jose E. Gonzalez; Haematology
city: Christchurch
country: New Zealand
facility: Canterbury Health Laboratories; Haematology
city: Newtown
country: New Zealand
facility: Wellington Hospital; Wellington Blood and Cancer Centre
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne; Klinika Hematologii i Transplantologii
city: Lublin
country: Poland
facility: Katedra i Klinika Hematoonkologii i Transplantacji Szpiku; Uniwersytetu Medycznego w Lublinie
city: Warszawa
country: Poland
facility: Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Lymphoma Dept.
city: Wroclaw
country: Poland
facility: Medical Uni of Wroclaw; Hematology
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria; Servico de Hematologia e Transplantacao de Medula
city: Porto
country: Portugal
facility: IPO do Porto; Servico de Onco-Hematologia
city: Moscow
country: Russian Federation
facility: N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis
city: Moscow
country: Russian Federation
facility: City Clinical Hospital After Botkin; Hematology
city: Moscow
country: Russian Federation
facility: Haematology Research Center; Haematology
city: Penza
country: Russian Federation
facility: Penza Regional Oncology Dispensary
city: Perm
country: Russian Federation
facility: Clinical MSCh No1
city: Saint-Petersburg
country: Russian Federation
facility: St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta
city: Bratislava
country: Slovakia
facility: National Oncology Inst. ; Dept. of Haematology
city: Bratislava
country: Slovakia
facility: University Hospital; Clinic of Hematology & Transfusiology
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron; Servicio de Hematologia
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa; Servicio de Hematologia
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro; Servicio de Hematologia
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca;Servicio de Hematologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio; Servicio de Hematologia
city: Toledo
country: Spain
facility: Complejo Hospitalario de Toledo- H. Virgen de la Salud; Servicio de Hematología
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
city: Ankara
country: Turkey
facility: Hacettepe Uni Medical Faculty; Hematology
city: Istanbul
country: Turkey
facility: Istanbul University Cerrahpasa Medical Faculty; Hematology Department
city: Izmir
country: Turkey
facility: Dokuz Eylul Uni ; Hematology
city: Izmir
country: Turkey
facility: Ege University ARGEFAR
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.