Rituximab With or Without Ibrutinib for Patients With Advanced Follicular Lymphoma

NCT ID: NCT02451111

Last Updated: 2024-03-13

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 190 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-11-06
• Study Completion Date: 2023-07-15

Brief Summary

Follicular lymphomas FL has been traditionally approached either by an initial watch and wait policy in the asymptomatic patient, or with single agent treatments with the purpose of maintaining a good quality of life for a prolonged time.The combination of rituximab and ibrutinib has been tested in clinical trials and appeared to be well tolerated and active. Since ibrutinib seems to achieve better results when administered for prolonged time as shown in CLL, the investigators have chosen to compare its combination with rituximab to the prolonged rituximab-only schedule that was already shown to be very active in the SAKK 35/03 trial.

The aim of the study is to investigate the efficacy, safety and tolerability of the treatment combination of Ibrutinib and Rituximab for patients with advanced follicular lymphoma in need of therapy.

Detailed Description

Follicular lymphomas FL has been traditionally approached either by an initial watch and wait policy in the asymptomatic patient, or with single agent treatments with the purpose of maintaining a good quality of life for a prolonged time.

During the last decades, treatment strategies have changed due to the continuous development and introduction of novel therapeutic approaches (including immunotherapy with interferon-alpha or monoclonal antibodies, the combination of immunotherapy with chemotherapy, and radioimmunotherapy with radiolabeled monoclonal antibodies).

For the asymptomatic patients with advanced-stage, but low tumor burden, randomized studies have confirmed that systemic treatment can be deferred until development of symptoms or organ failure (which generally occurred within 2-3 years from diagnosis) without any overall survival impairment and a watchful waiting policy has long remained a widely accepted approach.

For the symptomatic patients with more advanced tumor burden, in need of initial treatment, the combination of rituximab and chemotherapy, possibly followed by rituximab maintenance became a new standard in many countries.

In this setting of a chemotherapy-free strategy, the clinical study of rituximab combinations with other immunotherapies or with novel targeted agents is obvious relevant. Promising results have also been reported with the combination of rituximab and lenalidomide.

The combination of rituximab and ibrutinib has been tested in clinical trials and appeared to be well tolerated and active. Since ibrutinib seems to achieve better results when administered for prolonged time as shown in CLL, the investigators have chosen to compare its combination with rituximab to the prolonged rituximab-only schedule that was already shown to be very active in the SAKK 35/03 trial.

SAKK has a long tradition in treatment of FL patients with chemotherapy-free treatment based on rituximab. This is a worldwide special situation, which creates cooperation between important partners for clinical trials in this area.

The aim of the study is to investigate the efficacy, safety and tolerability of the treatment combination of Ibrutinib and Rituximab for patients with advanced follicular lymphoma in need of therapy.

Conditions

Follicular Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Rituximab/Ibrutinib

Ibrutinib capsules for 24 months (104 weeks) daily (always at the same time) in a dose of 560 mg (4 x 140 mg capsules)

Group Type: ACTIVE_COMPARATOR

Ibrutinib

Intervention Type: DRUG

Patients will be instructed by the Investigator to take the amount of 560 mg Ibrutinib/Placebo (4 x 140 mg capsules) orally once daily with a glass of water at approximately the same time every day.

Rituximab

Intervention Type: DRUG

Rituximab 375 mg/m2 has to be administered i.v. for the first four (4) infusions in all patients. After i.v. administration of Rituximab for the induction therapy, the administration mode can be changed to s.c. (1400 mg) in the maintenance phase dependent on the local standard of care.

Rituximab/Placebo

Placebo as comparator for 24 months (4 capsules daily always at the same time)

Group Type: PLACEBO_COMPARATOR

Rituximab

Intervention Type: DRUG

Rituximab 375 mg/m2 has to be administered i.v. for the first four (4) infusions in all patients. After i.v. administration of Rituximab for the induction therapy, the administration mode can be changed to s.c. (1400 mg) in the maintenance phase dependent on the local standard of care.

Interventions

Ibrutinib

Patients will be instructed by the Investigator to take the amount of 560 mg Ibrutinib/Placebo (4 x 140 mg capsules) orally once daily with a glass of water at approximately the same time every day.

Intervention Type: DRUG

Rituximab

Rituximab 375 mg/m2 has to be administered i.v. for the first four (4) infusions in all patients. After i.v. administration of Rituximab for the induction therapy, the administration mode can be changed to s.c. (1400 mg) in the maintenance phase dependent on the local standard of care.

Intervention Type: DRUG

Other Intervention Names

Imbruvica®; MabThera®

Eligibility Criteria

Inclusion Criteria

• Written informed consent according to ICH/GCP guidelines
• Histologically confirmed FL CD20+; grade 1, 2, 3a; stage III+IV; stage II not suitable for radiotherapy; all FLIPI
• Tumor specimens (slides or block) available for pathological review
• In need of systemic therapy (at least one of the following indications must be fulfilled):

• Symptomatic disease
• Bulky disease (≥ 6 cm)
• Steady, clinically significant progression over at least 3 months of any tumor lesion
• B-symptoms (weight loss > 10% in 6 months, drenching night sweats, fever > 38°C not due to infection)
• Anemia (hemoglobin < 100 g/L) or thrombocytopenia (platelets 50-100 x 109/L) due to lymphoma
• At least one two-dimensionally measurable lesion with a longest diameter (LDi) ≥ 15 mm in contrast-enhanced 18F-FDG PET/CT* scan
• FDG-avid tumor lesion in contrast-enhanced 18F-FDG PET/CT* scan
• Age 18-85 years
• WHO performance status 0-2
• Adequate bone marrow function:

• Absolute neutrophil count (ANC) > 1.0 x 109/L independent of growth factor support
• Platelets ≥ 100 x 109/L or ≥ 50 x 109/L if bone marrow involvement independent of transfusion support in either situation
• Adequate hepatic function:

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
• Adequate renal function:

• Serum creatinine ≤ 2 x ULN and corrected calculated creatinine clearance ≥ 40 mL/min/1.73m2.
• Women of childbearing potential have a negative serum (beta-human chorionic gonadotropin) or urine pregnancy test at Screening.
• Patient compliance and geographic proximity allow proper staging and follow-up.

Exclusion Criteria

• Tumor bulk requiring fast response
• Known central nervous system lymphoma
• Previous systemic FL therapies
• Major surgery 4 weeks prior to randomization
• Previous or concomitant malignancy diagnosed within 3 years with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer
• History of stroke or intracranial hemorrhage within 6 months prior to randomization
• Clinically significant cardiovascular diseases such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
• Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (i.v.) antibiotics
• Concomitant diseases that require anticoagulation with warfarin or equivalent vitamin K antagonists (eg. phenprocoumon), factor Xa inhibitors (e.g. rivaroxaban, apixaban), direct thrombin inhibitors (e.g. dabigatran) or platelet inhibitors/antiplatelet agents. Aspirin is allowed (up to 300 mg/d).
• Concomitant diseases that require treatment with strong or moderate CYP3A inhibitors (see http://medicine.iupui.edu/clinpharm/ddis/clinical-table/)
• Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information or known hypersensitivity to trial drugs
• Concurrent treatment with other experimental drugs or other anticancer therapy, treatment in a clinical trial within 30 days prior to trial entry
• Vaccinated with live, attenuated vaccines 4 weeks prior to randomization
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of Ibrutinib capsules, or put the study outcomes at undue risk
• Psychiatric disorder precluding understanding information of trial related topics, giving informed consent or interfering with compliance for oral drug intake
• Women who are pregnant or breastfeeding
• Patients regularly taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to Prednisone ≤ 15 mg/day for indications other than lymphoma or lymphoma-related symptoms

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Nordic Lymphoma Group

NETWORK

Sponsor Role: collaborator

Swiss Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Emanuele Zucca, Prof

Role: STUDY_CHAIR

Oncology Institute of Southern Switzerland IOSI, Bellinzona

Bjørn Østenstad, MD

Role: STUDY_CHAIR

Oslo University Hospital

Björn Wahlin, MD

Role: STUDY_CHAIR

Karolinska University Hospital, Stockholm

Locations

Akademisches Lehrkrankenhaus Feldkirch

Feldkirch, , Austria

Aalborg Universitetshospital

Aalborg, , Denmark

Aarhus University Hospital

Aarhus, , Denmark

Rigshospitalet

Copenhagen, , Denmark

Odense Universitetshospital

Odense C, , Denmark

Helsinki University Hospital

Helsinki, , Finland

Kuopio University Hospital

Kuopio, , Finland

University Hospital Tampere Radius

Tampere, , Finland

Turku University Hospital

Turku, , Finland

Haukeland University Hospital

Bergen, , Norway

Oslo University Hospital

Oslo, , Norway

Stavanger University Hospital

Stavanger, , Norway

Universitetssykehuset i Nord-Norge

Tromsø, , Norway

Sunderby Hospital

Luleå, , Sweden

Skanes Universitetssjukhus

Lund, , Sweden

Örebro University Hospital

Örebro, , Sweden

Karolinska University Hospital

Solna, , Sweden

Karolinska University Hospital

Stockholm, , Sweden

University Hospital of Umeå

Umeå, , Sweden

Hirslanden Klinik Aarau

Aarau, , Switzerland

Kantonspital Aarau

Aarau, , Switzerland

Zuger Kantonsspital

Baar, , Switzerland

Kantonsspital Baden

Baden, , Switzerland

St. Claraspital AG

Basel, , Switzerland

Universitaetsspital Basel

Basel, , Switzerland

Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli

Bellinzona, , Switzerland

Inselspital, Bern

Bern, , Switzerland

Spitalzentrum Oberwallis - Brig

Brig, , Switzerland

Kantonsspital Bruderholz

Bruderholz, , Switzerland

Hopitaux Universitaires de Geneve

Geneva, , Switzerland

Centre de Chimiothérapie Anti-Cancéreuse SA (CCAC)

Lausanne, , Switzerland

Kantonsspital Baselland

Liestal, , Switzerland

Kantonsspital Luzern

Luzerne, , Switzerland

Spital Thurgau (Kantonsspital Münserlingen und Frauenfeld)

Münsterlingen, , Switzerland

Kantonsspital Olten

Olten, , Switzerland

Kantonsspital - St. Gallen

Sankt Gallen, , Switzerland

Hôpital du Valais - CHCVR

Sion, , Switzerland

Spital STS AG

Thun, , Switzerland

Kantonsspital Winterthur

Winterthur, , Switzerland

Stadtspital Triemli

Zurich, , Switzerland

UniversitätsSpital Zürich

Zurich, , Switzerland

Onkozentrum Hirslanden

Zurich, , Switzerland

Countries

Austria; Denmark; Finland; Norway; Sweden; Switzerland

Other Identifiers

2015-001487-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SNCTP000001327

Identifier Type: OTHER

Identifier Source: secondary_id

SAKK 35/14

Identifier Type: -

Identifier Source: org_study_id