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

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ClinicalTrials.gov Identifier: NCT01292603
Recruitment Status : Completed
First Posted : February 9, 2011
Results First Posted : December 15, 2015
Last Update Posted : December 18, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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.

Condition or disease Intervention/treatment Phase
Lymphocytic Leukemia, Chronic Drug: Cyclophosphamide Drug: Fludarabine Drug: rituximab [MabThera] Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 240 participants
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 18, 2011
Actual Primary Completion Date : May 7, 2014
Actual Study Completion Date : November 17, 2017


Arm Intervention/treatment
Experimental: 1 Drug: Cyclophosphamide
Days 1-3 or Days 1-5 of cycles 1-6

Drug: Fludarabine
Days 1-3 or Days 1-5 of cycles 1-6

Drug: rituximab [MabThera]
After 4 cycles of intravenous MabThera without experiencing grade 3 or 4 infusion-related reactions. patients will receive 1 additional cycle of intravenous MabThera and 1 cycle of subcutaneous MabThera.

Experimental: 2 Drug: Cyclophosphamide
Days 1-3 or Days 1-5 of cycles 1-6

Drug: Fludarabine
Days 1-3 or Days 1-5 of cycles 1-6

Drug: rituximab [MabThera]
6 cycles of intravenous MabThera

Experimental: 3 Drug: Cyclophosphamide
Days 1-3 or Days 1-5 of cycles 1-6

Drug: Fludarabine
Days 1-3 or Days 1-5 of cycles 1-6

Drug: rituximab [MabThera]
One cycle of intravenous MabThera, followed by 5 cycles of subcutaneous MabThera




Primary Outcome Measures :
  1. Part 1: Subcutaneous Rituximab Dose Resulting in Trough Concentration (Ctrough) Levels Non-Inferior to Intravenous Rituximab [ Time Frame: 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 ]
    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.

  2. Part 2: Rituximab C Trough Levels at Cycle 5 [ Time Frame: +/- 25hours around the 28th day post the 5th Cycle of Rituximab administration ]
    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.


Secondary Outcome Measures :
  1. Part 2: Observed Area Under the Serum Concentration-Curve (AUC) of Rituximab at Cycle 6 [ Time Frame: 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 ]

    AUC values were calculated by numerical integration using the linear trapezoidal rule. AUC levels were analyzed using the model below:

    Ln(AUC) = μ + τi + BlTLij + εij wherein, Ln is the natural log, μ denotes the overall mean effect, τi the effect in each treatment group, BlTLij the tumor load at baseline for each patient and εij a random error variable with normal distribution and mean 0. The treatment effect therein was based on a contrast statement in the model to calculate 90 % confidence intervals for ln(AUC SC)- ln(AUC IV).


  2. Part 2: Maximum Observed Concentration (Cmax) of Rituximab at Cycle 6 [ Time Frame: 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 ]
    Cmax was obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of rituximab in the blood samplings.

  3. Part 2: Time to Cmax (Tmax) of Rituximab at Cycle 6 [ Time Frame: 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 ]
    Multiple blood samples were obtained at pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6 in Rituximab IV arm, and at pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6 in Rituximab SC arm and time to peak plasma concentration of rituximab was determined.

  4. Part 2: Terminal Half-Life of Rituximab at Cycle 6 [ Time Frame: 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 ]
    The terminal half-life (t1/2) of rituximab is defined as the time required for the plasma concentration of rituximab to reach half of its original concentration.

  5. Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration [ Time Frame: Days 4 to 5 in Cycle 6 ]
    In part 1 of the trial, upon completion of dosing in cycle 6, participants and their treating nurses were asked whether they have a preference of dosing route, IV vs SC

  6. Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV [ Time Frame: Days 4-5 in Cycle 6 ]

    Physicians and nurses who administered rituximab were asked to answer the following question: " If used in routine practice, on average, how much staff time could be saved with each administration of rituximab SC as compared to rituximab IV? (Please do not consider the time needed for the first IV administration, consider only the subsequent ones). Percentage of participants with specified answers were reported.

    • A- Less than 1 hour
    • B- At least 1 hour but less than 2 hours
    • C- At least 2 hours but less than 3 hours
    • D- At least 3 hours but less than 4 hours
    • E- 4 or more hours

  7. Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV [ Time Frame: Days 4-5 in Cycle 6 ]

    Physicians and nurses who administered rituximab were asked to answer the following question: Which formulation of rituximab (SC or IV) do you think is more convenient? with pre-specified responses as below. Percentage of participants with specified answers were reported.

    • A - Rituximab SC is much more convenient.
    • B - Rituximab SC is a little more convenient.
    • C - Both formulations are equally convenient.
    • D - Rituximab IV is a little more convenient.
    • E - Rituximab IV is much more convenient

  8. Part 1: Percentage of Participants With Anti-Rituximab Antibodies [ Time Frame: Predose at Cycles 5 and 6 and at each follow up visit until 24 months after the last dose ]
    Blood samples for the assessment of antibodies against rituximab (HACAs) were drawn pre-dose at Cycle 5 and Cycle 6 in Part 1 and at each follow up visit until 24 months after the last dose.

  9. Part 2: Percentage of Participants With Anti-Rituximab Antibodies [ Time Frame: 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. ]
    In Part 2, samples for the HACA assay were collected at each treatment cycle prior to the administration of rituximab and at each follow-up visit until 24 months after the last dose of rituximab.

  10. Part 1: Total Cluster Differentiation19 Positive (CD19+) B-Cell Counts by Visit [ Time Frame: 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 ]
    CD 19 is a surface antigen (protein) present on B-lymphocytes.

  11. Part 1: Percentage of Participants With Total B-Cell Depletion by Visit [ Time Frame: 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 ]
    Total B-cell depletion (normal B-cell plus Malignant B-cell depletion) was defined for each individual participant when the sum of CD5-/CD19+ (normal B-cells) and CD5+/CD19+ (malignant B-cells) cell counts decreased below 80 cells/μL.

  12. Part 2: Total CD19+ B-Cell Counts by Visit [ Time Frame: 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 ]
    CD 19 is a surface antigen (protein) present on B-lymphocytes.

  13. Part 2: Percentage of Participants With Total B-Cell Depletion by Visit [ Time Frame: 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 ]
    Total B-cell depletion (normal B-cell plus Malignant B-cell depletion) was defined for each individual participant when the sum of CD5-/CD19+ (normal B-cells) and CD5+/CD19+ (malignant B-cells) cell counts decreased below 80 cells/μL.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01292603


  Hide Study Locations
Locations
Argentina
Fundaleu; Haematology
Buenos Aires, Argentina, C1114AAN
Cemic; Haematology
Buenos Aires, Argentina, C1431FWO
HOSPITAL PRIVADO - CENTRO MEDICO DE CÓRDOBA; Dpto Oncología
Córdoba, Argentina, 5016
Australia, New South Wales
St George Hospital; Department of Haematology
Kogarah, New South Wales, Australia, 2217
Australia, Queensland
Royal Brisbane and Women'S Hospital; Haematology
Herston, Queensland, Australia, 4029
Australia, South Australia
Ashford Cancer Center Research
Kurralta Park, South Australia, Australia, 5037
Queen Elizabeth Hospital; Haematology
Woodville South, South Australia, Australia, 5011
Australia, Victoria
St Vincent'S Hospital; Haematology
Fitzroy, Victoria, Australia, 3065
Frankston Hospital; Oncology/Haematology
Frankston, Victoria, Australia, 3199
Brazil
Hospital da Cidade de Passo Fundo; Centro de Pesquisa em Oncologia
Passo Fundo, RS, Brazil, 99010-260
Hospital Mae de Deus
Porto Alegre, RS, Brazil, 90470-340
Hospital Sirio Libanes; Centro de Oncologia
Sao Paulo, SP, Brazil, 01308-050
Hospital das Clinicas - FMUSP
Sao Paulo, SP, Brazil, 05403-000
Canada, Nova Scotia
Queen Elizabeth II Health Sciences Centre; Oncology
Halifax, Nova Scotia, Canada, B3H 2Y9
Canada, Quebec
McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology
Montreal, Quebec, Canada, H3T 1E2
Centre de sante et de services sociaux Rimouski Neigette
Rimouski, Quebec, Canada, G5L 5T1
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke, Quebec, Canada, J1H 5N4
Chile
Instituto Nacional del Cancer
Santiago, Chile, 8380000
Centro Internacional de Estudios Clínicos (CIEC)
Santiago, Chile, 8420383
Croatia
Clinical Hospital Merkur; Dept of Haematology
Zagreb, Croatia, 10000
University Hospital Center Zagreb; Haematology Department
Zagreb, Croatia, 10000
Czechia
Fakultni nemocnice Brno; Interni hematoonkologicka klinika
Brno, Czechia, 625 00
University Hospital and Medical School; IV.Dept. of Internal Medicine and Hematology
Hradec Kralove, Czechia, 500 05
Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK
Praha 2, Czechia, 128 08
France
Centre Francois Baclesse
Caen, France, 14076
Institut J Paolii Calmettes; Onco Hematologie 1
Marseille, France, 13273
Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)
Paris, France, 75475
Hopital Robert Debre; Hematologie Clinique
Reims, France, 51092
Hopitaux De Brabois; Hematologie Medecine Interne
Vandoeuvre Les Nancy, France, 54511
Germany
Onkologische Schwerpunktpraxis Kurfürstendamm
Berlin, Germany, 10707
Onkologischer Schwerpunkt am Oskar-Helene-Heim; Dres. Herrenberger, Keitel-Wittig u. Kirsch
Berlin, Germany, 14195
BAG Freiberg-Richter, Jacobasch, Illmer, Wolf
Dresden, Germany, 01307
Klinikum Frankfurt Medizinische Klinik I
Frankfurt an der Oder, Germany, 15236
Universitätsklinikum Greifswald Klinik für Innere Medizin C und Poliklinik
Greifswald, Germany, 17475
Onkologische Schwerpunktpraxis Dres. Bernd Gaede, Hans-Ulrich Ehlers, Ulrike Rodewig u.w.
Hannover, Germany, 30171
Gemeinschaftspraxis Dr. Siehl & Dr. Soeling
Kassel, Germany, 34119
Klinik der Uni zu Köln; Klinik für Innere Medizin
Köln, Germany, 50924
K&K Studien GbR
Landshut, Germany, 84028
Onkologische Schwerpunktpraxis Lübeck
Lübeck, Germany, 23562
Gemeinschaftspraxis Fr. Dr. med. Balser & Hr. Dr. med. Weidenbach
Marburg, Germany, 35037
Klinikum Grosshadern der LMU
Muenchen, Germany, 81377
Medizinisches Versorgungszentrum MOP
München, Germany, 80335
Praxis Dr.med. Peter Schmidt
Neunkirchen/Saar, Germany, 66538
Prosper-Hospital, Medizinische Klinik I
Recklinghausen, Germany, 45659
Greece
Laiko General Hospital of Athens; A Propedeutical Clinic of Internal Medicine
Athens, Greece, 115 27
Papageorgiou General Hospital of Thessaloniki; Hematology Clinic
Thessaloniki, Greece, 54629
Italy
IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica
Meldola, Emilia-Romagna, Italy, 47014
Az. Osp. S. Maria Delle Croci; U.O. Di Ematologia
Ravenna, Emilia-Romagna, Italy, 48100
Ospedale Infermi Di Rimini; Unità Operativa di Oncologia e Oncoematologia
Rimini, Emilia-Romagna, Italy, 47900
A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica
Udine, Friuli-Venezia Giulia, Italy, 33100
Istituto S. Raffaele Monte Tabor; Divisione Ematologia E Utmo
Milano, Lombardia, Italy, 20132
ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA; Struttura Complessa di Ematologia
Milano, Lombardia, Italy, 20162
Univ. Piemonte Est Amedeo Avogadro; Div.Ematologia- Dip.Clinica Med.Sperim.& Ircad
Novara, Piemonte, Italy, 28100
Policlinico G. B. Rossi; Divisione Di Ematologia
Verona, Veneto, Italy, 37134
Mexico
Centro Estatal De Cancerologia De Chihuahua; Servicio De Hematologia Banco De Sangre
Chihuahua, Mexico, 31000
Hospital General De Culiacan; Servicio De Hematologia
Culiacan, Mexico, 80230
Hospital Universitario Dr. Jose E. Gonzalez; Haematology
Monterrey, Mexico, 64460
New Zealand
Canterbury Health Laboratories; Haematology
Christchurch, New Zealand, 8011
Wellington Hospital; Wellington Blood and Cancer Centre
Newtown, New Zealand, 6021
Poland
Uniwersyteckie Centrum Kliniczne; Klinika Hematologii i Transplantologii
Gdansk, Poland, 80-952
Katedra i Klinika Hematoonkologii i Transplantacji Szpiku; Uniwersytetu Medycznego w Lublinie
Lublin, Poland, 20-081
Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Lymphoma Dept.
Warszawa, Poland, 02-781
Medical Uni of Wroclaw; Hematology
Wroclaw, Poland, 50-367
Portugal
Hospital de Santa Maria; Servico de Hematologia e Transplantacao de Medula
Lisboa, Portugal, 1600
IPO do Porto; Servico de Onco-Hematologia
Porto, Portugal, 4200-072
Russian Federation
N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis
Moscow, Russian Federation, 115478
City Clinical Hospital After Botkin; Hematology
Moscow, Russian Federation, 125101
Haematology Research Center; Haematology
Moscow, Russian Federation, 125167
Penza Regional Oncology Dispensary
Penza, Russian Federation, 440071
Clinical MSCh No1
Perm, Russian Federation, 614077
St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta
Saint-Petersburg, Russian Federation, 197022
Slovakia
National Oncology Inst. ; Dept. of Haematology
Bratislava, Slovakia, 833 10
University Hospital; Clinic of Hematology & Transfusiology
Bratislava, Slovakia, 851 07
Spain
Hospital Universitari Vall d'Hebron; Servicio de Hematologia
Barcelona, Spain, 08035
Hospital Universitario de la Princesa; Servicio de Hematologia
Madrid, Spain, 28006
Hospital Universitario Puerta de Hierro; Servicio de Hematologia
Madrid, Spain, 28222
Hospital Clinico Universitario de Salamanca;Servicio de Hematologia
Salamanca, Spain, 37007
Hospital Universitario Virgen del Rocio; Servicio de Hematologia
Sevilla, Spain, 41013
Complejo Hospitalario de Toledo- H. Virgen de la Salud; Servicio de Hematología
Toledo, Spain, 45004
Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
Valencia, Spain, 46010
Turkey
Hacettepe Uni Medical Faculty; Hematology
Ankara, Turkey, 06100
Istanbul University Cerrahpasa Medical Faculty; Hematology Department
Istanbul, Turkey, 34098
Dokuz Eylul Uni ; Hematology
Izmir, Turkey, 35100
Ege University ARGEFAR
Izmir, Turkey, 35100
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01292603     History of Changes
Other Study ID Numbers: BO25341
2010-021380-32 ( EudraCT Number )
First Posted: February 9, 2011    Key Record Dates
Results First Posted: December 15, 2015
Last Update Posted: December 18, 2017
Last Verified: December 2017

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Cyclophosphamide
Fludarabine phosphate
Rituximab
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites