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

Lymphocytic Leukemia, Chronic Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01292603
• Other study ID #: BO25341
• Secondary ID: 2010-021380-32
• Status: Completed
• Phase: Phase 1
• Start date: April 18, 2011
• Est. completion date: November 17, 2017

Study information

• Verified date: November 2018
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 240
• Est. completion date: November 17, 2017
• Est. primary completion date: May 7, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphocytic Leukemia, Chronic

Intervention

Drug:
• Cyclophosphamide
Days 1-3 or Days 1-5 of cycles 1-6
• Fludarabine
Days 1-3 or Days 1-5 of cycles 1-6
• rituximab [MabThera]
One cycle of intravenous MabThera, followed by 5 cycles of subcutaneous MabThera
• 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.
• rituximab [MabThera]
6 cycles of intravenous MabThera

Locations

Country	Name	City	State
Argentina	Cemic; Haematology	Buenos Aires
Argentina	Fundaleu; Haematology	Buenos Aires
Argentina	HOSPITAL PRIVADO - CENTRO MEDICO DE CÓRDOBA; Dpto Oncología	Córdoba
Australia	St Vincent'S Hospital; Haematology	Fitzroy	Victoria
Australia	Frankston Hospital; Oncology/Haematology	Frankston	Victoria
Australia	Royal Brisbane and Women'S Hospital; Haematology	Herston	Queensland
Australia	St George Hospital; Department of Haematology	Kogarah	New South Wales
Australia	Ashford Cancer Center Research	Kurralta Park	South Australia
Australia	Queen Elizabeth Hospital; Haematology	Woodville South	South Australia
Brazil	Hospital da Cidade de Passo Fundo; Centro de Pesquisa em Oncologia	Passo Fundo	RS
Brazil	Hospital Mae de Deus	Porto Alegre	RS
Brazil	Hospital das Clinicas - FMUSP	Sao Paulo	SP
Brazil	Hospital Sirio Libanes; Centro de Oncologia	Sao Paulo	SP
Canada	Queen Elizabeth II Health Sciences Centre; Oncology	Halifax	Nova Scotia
Canada	McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology	Montreal	Quebec
Canada	Centre de sante et de services sociaux Rimouski Neigette	Rimouski	Quebec
Canada	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec
Chile	Centro Internacional de Estudios Clínicos (CIEC)	Santiago
Chile	Instituto Nacional del Cancer	Santiago
Croatia	Clinical Hospital Merkur; Dept of Haematology	Zagreb
Croatia	University Hospital Center Zagreb; Haematology Department	Zagreb
Czechia	Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika	Brno
Czechia	University Hospital and Medical School; IV.Dept. of Internal Medicine and Hematology	Hradec Kralove
Czechia	Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK	Praha 2
France	Centre Francois Baclesse	Caen
France	Institut J Paolii Calmettes; Onco Hematologie 1	Marseille
France	Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)	Paris
France	Hopital Robert Debre; Hematologie Clinique	Reims
France	Hopitaux De Brabois; Hematologie Medecine Interne	Vandoeuvre Les Nancy
Germany	Onkologische Schwerpunktpraxis Kurfürstendamm	Berlin
Germany	Onkologischer Schwerpunkt am Oskar-Helene-Heim; Dres. Herrenberger, Keitel-Wittig u. Kirsch	Berlin
Germany	BAG Freiberg-Richter, Jacobasch, Illmer, Wolf; Gemeinschaftspraxis Hämatologie-Onkologie	Dresden
Germany	Klinikum Frankfurt; Medizinische Klinik I	Frankfurt an der Oder
Germany	Universitätsklinikum Greifswald Klinik für Innere Medizin C und Poliklinik	Greifswald
Germany	Onkologische Schwerpunktpraxis Dres. Bernd Gaede, Hans-Ulrich Ehlers, Ulrike Rodewig u.w.	Hannover
Germany	Gemeinschaftspraxis Dr. Siehl & Dr. Soeling	Kassel
Germany	Klinik der Uni zu Köln; Klinik für Innere Medizin	Köln
Germany	K&K Studien GbR	Landshut
Germany	Onkologische Schwerpunktpraxis Lübeck	Lübeck
Germany	Gemeinschaftspraxis Fr. Dr. med. Balser & Hr. Dr. med. Weidenbach	Marburg
Germany	Klinikum Grosshadern der LMU	Muenchen
Germany	Medizinisches Versorgungszentrum MOP	München
Germany	Gemeinschaftspraxis Dr. med. Holger Klaproth / Dr. med. Anca Astrid Cura	Neunkirchen/Saar
Germany	Prosper-Hospital, Medizinische Klinik I	Recklinghausen
Greece	Laiko General Hospital of Athens; A Propedeutical Clinic of Internal Medicine	Athens
Greece	Papageorgiou General Hospital of Thessaloniki; Hematology Clinic	Thessaloniki
Italy	IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica	Meldola	Emilia-Romagna
Italy	ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA; Struttura Complessa di Ematologia	Milano	Lombardia
Italy	Istituto S. Raffaele Monte Tabor; Divisione Ematologia E Utmo	Milano	Lombardia
Italy	Univ. Piemonte Est Amedeo Avogadro; Div.Ematologia- Dip.Clinica Med.Sperim.& Ircad	Novara	Piemonte
Italy	Az. Osp. S. Maria Delle Croci; U.O. Di Ematologia	Ravenna	Emilia-Romagna
Italy	Ospedale Infermi Di Rimini; Unità Operativa di Oncologia e Oncoematologia	Rimini	Emilia-Romagna
Italy	A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica	Udine	Friuli-Venezia Giulia
Italy	Policlinico G. B. Rossi; Divisione Di Ematologia	Verona	Veneto
Mexico	Centro Estatal De Cancerologia De Chihuahua; Servicio De Hematologia Banco De Sangre	Chihuahua
Mexico	Hospital General De Culiacan; Servicio De Hematologia	Culiacan
Mexico	Hospital Universitario Dr. Jose E. Gonzalez; Haematology	Monterrey
New Zealand	Canterbury Health Laboratories; Haematology	Christchurch
New Zealand	Wellington Hospital; Wellington Blood and Cancer Centre	Newtown
Poland	Uniwersyteckie Centrum Kliniczne; Klinika Hematologii i Transplantologii	Gdansk
Poland	Katedra i Klinika Hematoonkologii i Transplantacji Szpiku; Uniwersytetu Medycznego w Lublinie	Lublin
Poland	Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Lymphoma Dept.	Warszawa
Poland	Medical Uni of Wroclaw; Hematology	Wroclaw
Portugal	Hospital de Santa Maria; Servico de Hematologia e Transplantacao de Medula	Lisboa
Portugal	IPO do Porto; Servico de Onco-Hematologia	Porto
Russian Federation	City Clinical Hospital After Botkin; Hematology	Moscow
Russian Federation	Haematology Research Center; Haematology	Moscow
Russian Federation	N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis	Moscow
Russian Federation	Penza Regional Oncology Dispensary	Penza
Russian Federation	Clinical MSCh No1	Perm
Russian Federation	St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta	Saint-Petersburg
Slovakia	National Oncology Inst. ; Dept. of Haematology	Bratislava
Slovakia	University Hospital; Clinic of Hematology & Transfusiology	Bratislava
Spain	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona
Spain	Hospital Universitario de la Princesa; Servicio de Hematologia	Madrid
Spain	Hospital Universitario Puerta de Hierro; Servicio de Hematologia	Madrid
Spain	Hospital Clinico Universitario de Salamanca;Servicio de Hematologia	Salamanca
Spain	Hospital Universitario Virgen del Rocio; Servicio de Hematologia	Sevilla
Spain	Complejo Hospitalario de Toledo- H. Virgen de la Salud; Servicio de Hematología	Toledo
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
Turkey	Hacettepe Uni Medical Faculty; Hematology	Ankara
Turkey	Istanbul University Cerrahpasa Medical Faculty; Hematology Department	Istanbul
Turkey	Dokuz Eylul Uni ; Hematology	Izmir
Turkey	Ege University ARGEFAR	Izmir

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Argentina,  Australia,  Brazil,  Canada,  Chile,  Croatia,  Czechia,  France,  Germany,  Greece,  Italy,  Mexico,  New Zealand,  Poland,  Portugal,  Russian Federation,  Slovakia,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Part 2: Observed Area Under the Serum Concentration-Curve (AUC) of Rituximab at 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 + ti + BlTLij + eij wherein, Ln is the natural log, µ denotes the overall mean effect, ti the effect in each treatment group, BlTLij the tumor load at baseline for each patient and eij 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).	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
Secondary	Part 2: Maximum Observed Concentration (Cmax) of Rituximab at 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.	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
Secondary	Part 2: Time to Cmax (Tmax) of Rituximab at 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.	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
Secondary	Part 2: Terminal Half-Life of Rituximab at 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.	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
Secondary	Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration	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	Days 4 to 5 in Cycle 6
Secondary	Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV	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)". The number of nurses that responded for both the IV and SC arms was 70. The number of physicians that responded for the IV and SC arms were 78 and 81 respectively.	Days 4-5 in Cycle 6
Secondary	Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV	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. The number of nurses that responded for both the IV and SC arms was 70. The number of physicians that responded for the IV and SC arms were 78 and 81 respectively.	Days 4-5 in Cycle 6
Secondary	Part 1: Percentage of Participants With Anti-Rituximab Antibodies	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.	Predose at Cycles 5 and 6 and at each follow up visit until 24 months after the last dose
Secondary	Part 2: Percentage of Participants With Anti-Rituximab Antibodies	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.	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.
Secondary	Part 1: Total Cluster Differentiation19 Positive (CD19+) B-Cell Counts by Visit	CD 19 is a surface antigen (protein) present on B-lymphocytes.	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
Secondary	Part 1: Percentage of Participants With Total B-Cell Depletion by 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.	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
Secondary	Part 2: Total CD19+ B-Cell Counts by Visit	CD 19 is a surface antigen (protein) present on B-lymphocytes.	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
Secondary	Part 2: Percentage of Participants With Total B-Cell Depletion by 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.	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