A Study to Evaluate Safety, Efficacy and Pharmacokinetics of Rituximab (MabThera/Rituxan) in Participants With Diffuse Large B Cell Lymphoma (DLBCL) or Follicular Lymphoma (FL)

Lymphoma Clinical Trial

Official title:

A Single Arm, Multicentre, Phase IIIB Study to Evaluate Safety, Efficacy and Pharmacokinetic (PK) of Subcutaneous (SC) Rituximab Administered During Induction Phase or Maintenance in Previously Untreated Patients With CD20+ Diffuse Large B Cell Lymphoma (DLBCL) or Follicular Lymphoma (FL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01889069
• Other study ID #: ML28881
• Secondary ID: 2013-000647-12
• Status: Completed
• Phase: Phase 3
• Start date: July 31, 2013
• Est. completion date: May 28, 2019

Study information

• Verified date: July 2020
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This single arm, multicenter study will evaluate the safety, efficacy and pharmacokinetic (PK) of subcutaneous (SC) rituximab in previously untreated participants with cluster of differentiation 20 positive (CD20+) DLBCL or FL. In addition to standard chemotherapy, participants will receive at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 159
• Est. completion date: May 28, 2019
• Est. primary completion date: May 28, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Histologically confirmed, CD20+ DLBCL or CD20+ follicular non-Hodgkin's lymphoma (NHL) Grade 1, 2 or 3a, according to the World Health Organization (WHO) classification system

• Currently being treated with rituximab intravenously (IV) in the Induction or Maintenance period, having received at least one full dose of rituximab IV, defined as standard full dose of rituximab IV 375 milligrams per square-meter (mg/m^2) administered without interruption or early discontinuation (i.e. tolerability issues)

• Expectation and current ability for the participant to receive at least 4 additional cycles of treatment during the Induction period or 6 additional cycles of treatment during the Maintenance period (participants with follicular NHL)

• An International Prognostic Index (IPI) score of 1-4 or IPI score of 0 with bulky disease, defined as one lesion greater than or equal to (>=) 7.5 centimeters (cm), or Follicular Lymphoma International Prognostic Index (FLIPI) (low, intermediate or high risk) assessed before the first rituximab IV administration in Induction period

• At least one bi-dimensionally measurable lesion defined as >=1.5 cm in its largest dimension on computed tomography (CT) scan

• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (<=) 3

Exclusion Criteria:

• Transformed lymphoma or FL IIIB

• Primary central nervous system lymphoma, histologic evidence of transformation to a Burkitt lymphoma, primary effusion lymphoma, primary mediastinal DLBCL, DLBCL of the testis, or primary cutaneous DLBCL

• History of other malignancy

• Ongoing corticosteroid use greater than (>) 30 milligrams per day (mg/day) of prednisone or equivalent

• Inadequate renal, hematologic, or hepatic function

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products

• Contraindications to any of the individual components of standard chemotherapy

• Other serious underlying medical conditions, which, in the Investigator's judgement, could impair the ability of the participant to participate in the study

• Recent major surgery (within 4 weeks prior to dosing, other than for diagnosis)

• Active hepatitis B virus (HBV), active hepatitis C virus (HCV) infection, or human immunodeficiency virus (HIV) infection

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Follicular
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• Rituximab
Rituximab will be administered at a dose of 1400 mg SC once a month for at least 4 doses during the Induction period, and at a dose of 1400 mg SC once every two months for at least 6 doses during the Maintenance period.
• Cyclophosphamide
Cyclophosphamide will be administered as per standard local practice as a part of standard chemotherapy regimen.
• Vincristine
Vincristine will be administered as per standard local practice as a part of standard chemotherapy regimen.
• Doxorubicin
Doxorubicin will be administered as per standard local practice as a part of standard chemotherapy regimen.
• Prednisone
Prednisone will be administered as per standard local practice as a part of standard chemotherapy regimen.
• Bendamustine
Bendamustine will be administered as per standard local practice as a part of standard chemotherapy regimen.

Locations

Country	Name	City	State
Italy	Ospedale Civile SS. Antonio E Biagio DI Alessandria; Ematologia	Alessandria	Piemonte
Italy	Ospedale Gen.Le Prov.Le 'C.G.Mazzoni'; Ematologia	Ascoli Piceno	Marche
Italy	Azienda Ospedaliera S.G. Moscati; Divisione Ematologia	Avellino	Campania
Italy	Asl ce - p.o. Avers; Uoc ematologia	Aversa	Campania
Italy	Irccs Ist. Tumori Giovanni Paolo Ii; Dipartimento Oncologia Medica	Bari	Puglia
Italy	Ospedale Roberto Binaghi; Centro trapianti di midollo osseo	Cagliari	Sardegna
Italy	Università Cattolica Del Sacro Cuore S.S. Giovanni Paolo Ii; Uoc Di Onco-Ematologia	Campobasso	Molise
Italy	A.O. San Sebastiano; U.O.C. Oncologia	Caserta	Campania
Italy	ARNAS Garibaldi; Ematologia	Catania	Sicilia
Italy	Ospedale di Civitanova Marche; Medicina Interna	Civitanova Marche	Marche
Italy	Ospedale Valduce;U.O.S. Oncologia Ed Ematologia	Como	Lombardia
Italy	ASST DI CREMA; U O Oncologia Medica	Crema	Lombardia
Italy	Azienda ospedaliera oo rr di foggi; Hematology	Foggia	Puglia
Italy	Osp. Santa Maria Goretti; Ematologia	Latina	Lazio
Italy	ASST DI LECCO; Oncologia Medica	Lecco	Lombardia
Italy	Ospedale di Macerata; Medicina Generale	Macerata	Marche
Italy	Az. Osp. Carlo Poma; Divisione Di Oncologia Medica	Mantova	Lombardia
Italy	Az. Osp. Papardo; Struttura Complessa Di Ematologia	Messina	Sicilia
Italy	Ist. Nazionale Per Lo Studio E Cura Dei Tumori; Div. Ematologia Trapianto Midollo Osseo Allogenico	Milano	Lombardia
Italy	Osp. San Raffaele; Dip. Di Oncoematologia	Milano	Lombardia
Italy	Seconda università degli studi di napoli; Medicina clinica e sperimentale magrassi - lanzara	Napoli	Campania
Italy	Univ. Piemonte Est Amedeo Avogadro; Div.Ematologia- Dip.Clinica Med.Sperim.& Ircad	Novara	Piemonte
Italy	Osp. San Francesco; Ematologia e CTMO	Nuoro	Sardegna
Italy	IOV - Istituto Oncologico Veneto - IRCCS; Oncologia Medica II	Padova	Veneto
Italy	ARNAS-Ospedale Civico Maurizio Ascoli; Unità Operativa di Oncologia Medica	Palermo	Sicilia
Italy	Azienda Uni Ria Policlinico P. Giaccone ; Divisione Di Ematologia E Trapianto	Palermo	Sicilia
Italy	Irccs Policlinico San Matteo; Divisione Di Ematologia	Pavia	Lombardia
Italy	Ospedale Santa Chiara; Unita Operativa Di Ematologia	Pisa	Toscana
Italy	USL 4 di Prato - Nuovo Ospeale di Prato	Prato	Toscana
Italy	Azienda Ospedaliera Bianchi-Melacrino-Morelli; Unità Operativa di Ematologia	Reggio Calabria	Calabria
Italy	Irccs Crob	Rionero in Vulture	Basilicata
Italy	Az. Osp. S. Camillo Forlanini; Uo Ematologia E Trapianti Di Midollo Osseo	Roma	Lazio
Italy	Azienda Ospedaliera S. Giovanni Addolorata; UOC Ematologia	Roma	Lazio
Italy	Ospedale S. Eugenio; Divisione Di Ematologia	Roma	Lazio
Italy	Regina Elena National Cancer Institute; Hematology	Roma	Lazio
Italy	Universita' Degli Studi La Sapienza-Ist.Di Ematologia; Dip Biot Cel e Ematol	Roma	Lazio
Italy	ASL Viterbo; Presidio Ospedaliero di Ronciglione; UOC Ematologia	Ronciglione	Lazio
Italy	Istituto Clinico Humanitas;U.O. Oncologia Medica Ed Ematologia	Rozzano	Lombardia
Italy	A.O. Santa Maria Terni; S.C. Oncoematologia	Terni	Umbria

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Administration-Associated Reactions (AAR)	AARs were defined as all adverse events (AEs) occurring within 24 hours of rituximab administration and which were considered related to study drug. AARs included infusion/injection-related reactions (IIRRs), injection-site reactions, administration site conditions and all symptoms thereof. Grading was completed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.	Baseline up to 54 months
Secondary	Percentage of Participants With At Least One Grade = 3 Treatment-Emergent Adverse Events (TEAEs)	An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with the treatment. An adverse event was therefore any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsened during the study were also considered as adverse events. Grading was completed according to the CTCAE, version 4.0.	Baseline up to 54 months
Secondary	Percentage of Participants With At Least One Grade = 3 Infusion/ Injection Related Reactions (IIRRs)	Grading of IIRRs was completed according to the CTCAE, version 4.0.	Baseline up to 54 months
Secondary	Percentage of Participants With At Least One Treatment-Emergent Serious Adverse Events	SAE was defined as any experience that suggested a significant hazard, contraindication, side effect, or precaution, and fulfilled any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/ birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here.	Baseline up to 54 months
Secondary	Percentage of Participants With Event-Free Survival (EFS) According to IWG Response Criteria	EFS was defined as the time from first dose of rituximab to first occurrence of progression or relapse, according to the International Working Group (IWG) response criteria or other country standards, or initiation of a non-protocol-specified anti-lymphoma therapy or death, whichever occurred first.	Day 1 up to first occurrence of progression or relapse, or initiation of a non-protocol-specified anti-lymphoma therapy or death, whichever occurs first (up to maximum 54 months)
Secondary	Percentage of Participants With Progression-Free Survival (PFS) According to IWG Response Criteria	PFS was defined as the time from first dose of rituximab to the first occurrence of disease progression or relapse, according to the International Working Group (IWG) response criteria or other country standards, or death from any cause, whichever occurred first.	Day 1 up to first occurrence of progression or relapse, or death, whichever occurs first (up to maximum 54 months)
Secondary	Percentage of Participants With Overall Survival (OS)	OS was defined as the time from first dose of rituximab to death from any cause.	Day 1 until death (up to maximum 54 months)
Secondary	Percentage of Participants With Disease-Free Survival (DFS) According to IWG Response Criteria	DFS assessed in participants achieving complete response (CR) including complete response unconfirmed (Cru) and was defined as the period from 4 to 8 weeks after end of Induction period up to relapse or death from any cause, whichever occured first.	From 4 to 8 weeks after end of Induction period up to relapse or death from any cause, whichever occurs first (up to maximum 54 months) (end of Induction period = up to 8 months)
Secondary	Percentage of Participants With Complete Response (CR) According to IWG Response Criteria	Complete response required: 1) the complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities, 2) all lymph nodes and nodal masses had regressed to normal size, 3) the spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and not be palpable on physical examination and 4) if the bone marrow was involved by lymphoma before treatment, the infiltrate was cleared on repeat bone marrow aspirate and biopsy of the same site. CR/unconfirmed (CRu) included those patients who fulfilled criteria 1 and 3 above as well as 1) a residual lymph node mass greater than 1.5 cm in greatest transverse diameter that regressed by more than 75% in the SPD and 2) indeterminate bone marrow. Response was assessed according to the IWG response criteria.	At 4 to 8 weeks after end of Induction period (end of Induction period = up to 8 months)
Secondary	FL: Plasma Trough Concentrations of Rituximab	FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. Pharmacokinetic (PK) data only collected for participants enrolled during Induction. During the induction phase each Cycle is 21 days.	Induction collection: Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, and Cycle 8 Predose on Day 1
Secondary	FL: Overall Geometric Least Square (LS) Mean Plasma Trough Concentrations of Rituximab	FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. PK data only collected for participants enrolled during Induction. During the induction phase each Cycle is 21 days.	Induction collection: Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, and Cycle 8 Predose on Day 1
Secondary	FL: Plasma Trough Concentrations of Rituximab in Participants With Complete Response/Complete Response Unconfirmed (CR/CRu)	FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. PK data only collected for participants enrolled during Induction. During the induction phase each Cycle is 21 days.	Induction collection: Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, and Cycle 8 Predose on Day 1
Secondary	DLBCL: Plasma Concentrations of Rituximab	DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.	Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
Secondary	DLBCL: Plasma Trough Concentrations of Rituximab	DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.	Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 pre-dose on Day 1
Secondary	DLBCL: Area Under the Plasma Concentration-Time Curve (AUC) of Rituximab	DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.	Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
Secondary	DLBCL: Maximum Plasma Concentration (Cmax) of Rituximab	DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.	Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
Secondary	DLBCL: Apparent Total Clearance (CL/F) of Rituximab	DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.	Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
Secondary	DLBCL: Plasma Trough Concentrations of Rituximab in Participants With Complete Response/Complete Response Unconfirmed (CR/CRu)	DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.	Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
Secondary	DLBCL: Overall Geometric Least Square (LS) Mean Plasma Trough Concentrations of Rituximab	DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.	Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
Secondary	DLBCL: Plasma Concentrations During Different Scheduling of Rituximab SC R-CHOP-14 or R-CHOP-21	Plasma concentrations of rituximab in participants with DLBCL by chemotherapy regimen cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 14 days (R-CHOP-14) or cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 21 days (R-CHOP-21) in the PK) population.DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.	Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
Secondary	Rituximab Administration Satisfaction Questionnaire (RASQ) Convenience and Satisfaction Domain Scores	Patient-assessed satisfaction was evaluated using RASQ. Participants were asked questions regarding convenience and satisfaction for rituximab SC. Each domain is scored on a scale of 0 to 100, with higher scores indicative of more positive feelings toward therapy. The score for each domain was averaged among all participants. DLBCL participants could be enrolled at cycle 2, cycle 3, or cycle 4. FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must be able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. Each Cycle is 21 days for DLBCL. Each Cycle 21 days during the Induction phase and 2 months during Maintenance phase for FL.	DLBCL: Cycle (C) 2, C3, C4, C5, C6, End of C8; FL: Induction: C3, C4, C5, C6, C8, Maintenance: C2, C3, C4, C5, C6, C7, C8, C10, C12, End of treatment (4-8 weeks after last dose)