Rituximab With or Without Ibrutinib for Patients With Advanced Follicular Lymphoma

Follicular Lymphoma Clinical Trial

Official title:

Rituximab With or Without Ibrutinib for Untreated Patients With Advanced Follicular Lymphoma in Need of Therapy. A Randomized, Double-blinded, SAKK and NLG Collaborative Phase II Trial.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02451111
• Other study ID #: SAKK 35/14
• Secondary ID: 2015-001487-19SN
• Status: Terminated
• Phase: Phase 2
• Start date: November 6, 2015
• Est. completion date: July 15, 2023

Study information

• Verified date: March 2024
• Source: Swiss Group for Clinical Cancer Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 190
• Est. completion date: July 15, 2023
• Est. primary completion date: December 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Follicular Lymphoma
• Lymphoma
• Lymphoma, Follicular

Intervention

Drug:
• 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.
• 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.

Locations

Country	Name	City	State
Austria	Akademisches Lehrkrankenhaus Feldkirch	Feldkirch
Denmark	Aalborg Universitetshospital	Aalborg
Denmark	Aarhus University Hospital	Aarhus
Denmark	Rigshospitalet	Copenhagen
Denmark	Odense Universitetshospital	Odense C
Finland	Helsinki University Hospital	Helsinki
Finland	Kuopio University Hospital	Kuopio
Finland	University Hospital Tampere Radius	Tampere
Finland	Turku University Hospital	Turku
Norway	Haukeland University Hospital	Bergen
Norway	Oslo University Hospital	Oslo
Norway	Stavanger University Hospital	Stavanger
Norway	Universitetssykehuset i Nord-Norge	Tromsø
Sweden	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
Switzerland	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	Genève 14
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	Hôpital du Valais - CHCVR	Sion
Switzerland	Kantonsspital - St. Gallen	St. Gallen
Switzerland	Spital STS AG	Thun
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Onkozentrum Hirslanden	Zürich
Switzerland	Stadtspital Triemli	Zürich
Switzerland	UniversitätsSpital Zürich	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
Swiss Group for Clinical Cancer Research	Nordic Lymphoma Group

Countries where clinical trial is conducted

Austria,  Denmark,  Finland,  Norway,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CR at 24 months determined by PET/CT scan by the IRR panel	The evaluation of CR is outlined according to Cheson Criteria.. Any assessment within a window of week 102 to week 118 (inclusive) will be considered as the 24 months response assessment for determining the CR status. In addition, the CR status will be determined as follows for these specific cases:	at 24 months
Secondary	CR at 30 months determined by PET/CT scan by the IRR panel		at 30 months
Secondary	MRD evaluation	MRD evaluation will be performed using real-time PCR (polymerase chain reaction) based methods in peripheral blood and bone marrow at baseline and week 106. The proportion of patients achieving MRD negativity will be calculated for each time point of interest.	baseline and week 106
Secondary	Overall response (OR)	OR is defined as either: the disappearance of all evidence of disease (CR); the regression of measurable disease with no new sites (PR)	at 24 weeks
Secondary	Duration of complete response (DUR)	The duration of CR will be calculated from when the criteria for CR are met, until documentation of relapse thereafter. Only patients with a CR will be included in this analysis.	at 12 or 24 weeks or thereafter
Secondary	Progression-free survival (PFS) (PFS)	PFS will be calculated from randomization until the first event of interest: disease progression or relapse according to criteria of Cheson et al. 2014; death from any cause	at 12 or 24 weeks or thereafter
Secondary	Event-free survival (EFS)	Event-free survival (time to treatment failure) will be calculated from randomization to premature discontinuation of trial treatment for any reason (e.g., insufficient response at first or second restaging at 12 or 24 weeks or at the third assessment at 52 weeks, disease progression, toxicity, patient preference, initiation of new treatment without documented progression, secondary malignancy or death).	12, 24 or 52 weeks
Secondary	Time to next anti-lymphoma therapy (TTNT)	This will be calculated from randomization until the start of the first off-trial anti-lymphoma treatment. Patients not receiving any off-trial anti-lymphoma treatment will be censored at the last follow-up visit.	at 12 or 24 weeks or thereafter
Secondary	Adverse Events (AEs)	AEs will be evaluated using the NCI CTCAE v4.0	record throughout treatment phase (until 30 days after last drug administration)