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Rituximab With or Without Ibrutinib for Patients With Advanced Follicular Lymphoma

Primary Purpose

Follicular Lymphoma

Status

Active

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Ibrutinib

Rituximab

About this trial

This is an interventional treatment trial for Follicular Lymphoma focused on measuring Rituximab, Ibrutinib, Follicular Lymphoma

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Akademisches Lehrkrankenhaus Feldkirch
Aalborg Universitetshospital
Aarhus University Hospital
Rigshospitalet
Odense Universitetshospital
Helsinki University Hospital
Kuopio University Hospital
University Hospital Tampere Radius
Turku University Hospital
Haukeland University Hospital
Oslo University Hospital
Stavanger University Hospital
Universitetssykehuset i Nord-Norge
Sunderby Hospital
Skanes Universitetssjukhus
Karolinska University Hospital
Karolinska University Hospital
University Hospital of Umeå
Örebro University Hospital
Hirslanden Klinik Aarau
Kantonspital Aarau
Zuger Kantonsspital
Kantonsspital Baden
St. Claraspital AG
Universitaetsspital Basel
Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
Inselspital, Bern
Spitalzentrum Oberwallis - Brig
Kantonsspital Bruderholz
Hopitaux Universitaires de Geneve
Centre de Chimiothérapie Anti-Cancéreuse SA (CCAC)
Kantonsspital Baselland
Kantonsspital Luzern
Spital Thurgau (Kantonsspital Münserlingen und Frauenfeld)
Kantonsspital Olten
Hôpital du Valais - CHCVR
Kantonsspital - St. Gallen
Spital STS AG
Kantonsspital Winterthur
Stadtspital Triemli
UniversitätsSpital Zürich
Onkozentrum Hirslanden

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Rituximab/Ibrutinib

Rituximab/Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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:

Secondary Outcome Measures

CR at 30 months determined by PET/CT scan by the IRR panel

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.

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)

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.

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

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).

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.

Adverse Events (AEs)

AEs will be evaluated using the NCI CTCAE v4.0

Full Information

NCT ID

NCT02451111

First Posted

May 19, 2015

Last Updated

March 7, 2023

Sponsor

Swiss Group for Clinical Cancer Research

Collaborators

Nordic Lymphoma Group

1. Study Identification

Unique Protocol Identification Number

NCT02451111

Brief Title

Rituximab With or Without Ibrutinib for Patients With Advanced Follicular Lymphoma

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.

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

November 6, 2015 (Actual)

Primary Completion Date

March 2024 (Anticipated)

Study Completion Date

December 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Swiss Group for Clinical Cancer Research

Collaborators

Nordic Lymphoma Group

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Follicular Lymphoma

Keywords

Rituximab, Ibrutinib, Follicular Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

190 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Rituximab/Ibrutinib

Arm Type

Active Comparator

Arm Description

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

Arm Title

Rituximab/Placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Ibrutinib

Other Intervention Name(s)

Imbruvica®

Intervention Description

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

Intervention Name(s)

Rituximab

Other Intervention Name(s)

MabThera®

Intervention Description

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.

Primary Outcome Measure Information:

Title

CR at 24 months determined by PET/CT scan by the IRR panel

Description

Time Frame

at 24 months

Secondary Outcome Measure Information:

Title

CR at 30 months determined by PET/CT scan by the IRR panel

Time Frame

at 30 months

Title

MRD evaluation

Description

Time Frame

baseline and week 106

Title

Overall response (OR)

Description

OR is defined as either: the disappearance of all evidence of disease (CR) the regression of measurable disease with no new sites (PR)

Time Frame

at 24 weeks

Title

Duration of complete response (DUR)

Description

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.

Time Frame

at 12 or 24 weeks or thereafter

Title

Progression-free survival (PFS) (PFS)

Description

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

Time Frame

at 12 or 24 weeks or thereafter

Title

Event-free survival (EFS)

Description

Time Frame

12, 24 or 52 weeks

Title

Time to next anti-lymphoma therapy (TTNT)

Description

Time Frame

at 12 or 24 weeks or thereafter

Title

Adverse Events (AEs)

Description

AEs will be evaluated using the NCI CTCAE v4.0

Time Frame

record throughout treatment phase (until 30 days after last drug administration)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Emanuele Zucca, Prof

Organizational Affiliation

Oncology Institute of Southern Switzerland IOSI, Bellinzona

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Bjørn Østenstad, MD

Organizational Affiliation

Oslo University Hospital

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Björn Wahlin, MD

Organizational Affiliation

Karolinska University Hospital, Stockholm

Official's Role

Study Chair

Facility Information:

Facility Name

Akademisches Lehrkrankenhaus Feldkirch

City

Feldkirch

ZIP/Postal Code

6800

Country

Austria

Facility Name

Aalborg Universitetshospital

City

Aalborg

ZIP/Postal Code

9000

Country

Denmark

Facility Name

Aarhus University Hospital

City

Aarhus

ZIP/Postal Code

8000

Country

Denmark

Facility Name

Rigshospitalet

City

Copenhagen

ZIP/Postal Code

2100

Country

Denmark

Facility Name

Odense Universitetshospital

City

Odense C

ZIP/Postal Code

5000

Country

Denmark

Facility Name

Helsinki University Hospital

City

Helsinki

ZIP/Postal Code

00029 HUS

Country

Finland

Facility Name

Kuopio University Hospital

City

Kuopio

ZIP/Postal Code

70029

Country

Finland

Facility Name

University Hospital Tampere Radius

City

Tampere

ZIP/Postal Code

33521

Country

Finland

Facility Name

Turku University Hospital

City

Turku

ZIP/Postal Code

20520

Country

Finland

Facility Name

Haukeland University Hospital

City

Bergen

ZIP/Postal Code

5021

Country

Norway

Facility Name

Oslo University Hospital

City

Oslo

ZIP/Postal Code

424

Country

Norway

Facility Name

Stavanger University Hospital

City

Stavanger

ZIP/Postal Code

4011

Country

Norway

Facility Name

Universitetssykehuset i Nord-Norge

City

Tromsø

ZIP/Postal Code

9038

Country

Norway

Facility Name

Sunderby Hospital

City

Luleå

ZIP/Postal Code

971 80

Country

Sweden

Facility Name

Skanes Universitetssjukhus

City

Lund

ZIP/Postal Code

221 85

Country

Sweden

Facility Name

Karolinska University Hospital

City

Solna

ZIP/Postal Code

17165

Country

Sweden

Facility Name

Karolinska University Hospital

City

Stockholm

ZIP/Postal Code

141 86

Country

Sweden

Facility Name

University Hospital of Umeå

City

Umeå

ZIP/Postal Code

901 85

Country

Sweden

Facility Name

Örebro University Hospital

City

Örebro

ZIP/Postal Code

701 85

Country

Sweden

Facility Name

Hirslanden Klinik Aarau

City

Aarau

ZIP/Postal Code

CH-5001

Country

Switzerland

Facility Name

Kantonspital Aarau

City

Aarau

ZIP/Postal Code

CH-5001

Country

Switzerland

Facility Name

Zuger Kantonsspital

City

Baar

ZIP/Postal Code

6340

Country

Switzerland

Facility Name

Kantonsspital Baden

City

Baden

ZIP/Postal Code

CH-5404

Country

Switzerland

Facility Name

St. Claraspital AG

City

Basel

ZIP/Postal Code

CH-4016

Country

Switzerland

Facility Name

Universitaetsspital Basel

City

Basel

ZIP/Postal Code

CH-4031

Country

Switzerland

Facility Name

Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli

City

Bellinzona

ZIP/Postal Code

6500

Country

Switzerland

Facility Name

Inselspital, Bern

City

Bern

ZIP/Postal Code

CH-3010

Country

Switzerland

Facility Name

Spitalzentrum Oberwallis - Brig

City

Brig

ZIP/Postal Code

3900

Country

Switzerland

Facility Name

Kantonsspital Bruderholz

City

Bruderholz

ZIP/Postal Code

CH-4101

Country

Switzerland

Facility Name

Hopitaux Universitaires de Geneve

City

Genève 14

ZIP/Postal Code

1211

Country

Switzerland

Facility Name

Centre de Chimiothérapie Anti-Cancéreuse SA (CCAC)

City

Lausanne

ZIP/Postal Code

1004

Country

Switzerland

Facility Name

Kantonsspital Baselland

City

Liestal

ZIP/Postal Code

4410

Country

Switzerland

Facility Name

Kantonsspital Luzern

City

Luzerne

ZIP/Postal Code

CH-6000

Country

Switzerland

Facility Name

Spital Thurgau (Kantonsspital Münserlingen und Frauenfeld)

City

Münsterlingen

ZIP/Postal Code

8596

Country

Switzerland

Facility Name

Kantonsspital Olten

City

Olten

ZIP/Postal Code

CH-4600

Country

Switzerland

Facility Name

Hôpital du Valais - CHCVR

City

Sion

ZIP/Postal Code

1951

Country

Switzerland

Facility Name

Kantonsspital - St. Gallen

City

St. Gallen

ZIP/Postal Code

CH-9007

Country

Switzerland

Facility Name

Spital STS AG

City

Thun

ZIP/Postal Code

CH-3600

Country

Switzerland

Facility Name

Kantonsspital Winterthur

City

Winterthur

ZIP/Postal Code

8401

Country

Switzerland

Facility Name

Stadtspital Triemli

City

Zürich

ZIP/Postal Code

8063

Country

Switzerland

Facility Name

UniversitätsSpital Zürich

City

Zürich

ZIP/Postal Code

8091

Country

Switzerland

Facility Name

Onkozentrum Hirslanden

City

Zürich

ZIP/Postal Code

CH-8032

Country

Switzerland

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Rituximab With or Without Ibrutinib for Patients With Advanced Follicular Lymphoma

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