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Follicular LymphomaPhase 2NCT02451111

Rituximab With or Without Ibrutinib for Patients With Advanced Follicular Lymphoma

A Phase 2 study testing Ibrutinib and Rituximab in people with Follicular Lymphoma, run by Swiss Cancer Institute at 42 sites in 6 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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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… Read more about this study

Who is it for?
Ages 18 to 85 years
Conditions the study is for
Follicular Lymphoma
What is being tested?
Ibrutinib and Rituximab
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
190 participants
Where
42 sitesin 6 countries
Study dates
6 Nov 2015to 15 Jul 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
Show all 23Show fewer
  • 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.

Who cannot join

  • 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
Show all 17Show fewer
  • 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

Trial locations and contacts

42 sites in 6 countries.

42 sites in 6 countries

Switzerland23 sites

  • Hirslanden Klinik Aarau

    Aarau, CH-5001

  • Kantonspital Aarau

    Aarau, CH-5001

  • Zuger Kantonsspital

    Baar, 6340

  • Kantonsspital Baden

    Baden, CH-5404

  • St. Claraspital AG

    Basel, CH-4016

  • Universitaetsspital Basel

    Basel, CH-4031

  • Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli

    Bellinzona, 6500

  • Inselspital, Bern

    Bern, CH-3010

  • Spitalzentrum Oberwallis - Brig

    Brig, 3900

  • Kantonsspital Bruderholz

    Bruderholz, CH-4101

  • Hopitaux Universitaires de Geneve

    Geneva, 1211

  • Centre de Chimiothérapie Anti-Cancéreuse SA (CCAC)

    Lausanne, 1004

  • Kantonsspital Baselland

    Liestal, 4410

  • Kantonsspital Luzern

    Luzerne, CH-6000

  • Spital Thurgau (Kantonsspital Münserlingen und Frauenfeld)

    Münsterlingen, 8596

  • Kantonsspital Olten

    Olten, CH-4600

  • Kantonsspital - St. Gallen

    Sankt Gallen, CH-9007

  • Hôpital du Valais - CHCVR

    Sion, 1951

  • Spital STS AG

    Thun, CH-3600

  • Kantonsspital Winterthur

    Winterthur, 8401

  • Stadtspital Triemli

    Zurich, 8063

  • UniversitätsSpital Zürich

    Zurich, 8091

  • Onkozentrum Hirslanden

    Zurich, CH-8032

Other trials in Switzerland

Sweden6 sites

  • Sunderby Hospital

    Luleå, 971 80

  • Skanes Universitetssjukhus

    Lund, 221 85

  • Örebro University Hospital

    Örebro, 701 85

  • Karolinska University Hospital

    Solna, 17165

  • Karolinska University Hospital

    Stockholm, 141 86

  • University Hospital of Umeå

    Umeå, 901 85

Other trials in Sweden

Denmark4 sites

  • Aalborg Universitetshospital

    Aalborg, 9000

  • Aarhus University Hospital

    Aarhus, 8000

  • Rigshospitalet

    Copenhagen, 2100

  • Odense Universitetshospital

    Odense C, 5000

Other trials in Denmark

Finland4 sites

  • Helsinki University Hospital

    Helsinki, 00029 HUS

  • Kuopio University Hospital

    Kuopio, 70029

  • University Hospital Tampere Radius

    Tampere, 33521

  • Turku University Hospital

    Turku, 20520

Other trials in Finland

Norway4 sites

  • Haukeland University Hospital

    Bergen, 5021

  • Oslo University Hospital

    Oslo, 424

  • Stavanger University Hospital

    Stavanger, 4011

  • Universitetssykehuset i Nord-Norge

    Tromsø, 9038

Other trials in Norway

Austria1 site

  • Akademisches Lehrkrankenhaus Feldkirch

    Feldkirch, 6800

Other trials in Austria

About this study

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.

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.

Read the 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.

Being tested
Ibrutinib, Rituximab
Keywords
Rituximab, Ibrutinib, Follicular Lymphoma
Medical subject headings
Lymphoma, Follicular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IbrutinibDrug

    Also called Imbruvica®

    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.

  • RituximabDrug

    Also called MabThera®

    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.

Study groups in NCT02451111
Study groupRoleWhat they receive
Rituximab/IbrutinibActive comparatorIbrutinib capsules for 24 months (104 weeks) daily (always at the same time) in a dose of 560 mg (4 x 140 mg capsules)
Receives: Drug: Ibrutinib; Drug: Rituximab
Rituximab/PlaceboPlacebo comparatorPlacebo as comparator for 24 months (4 capsules daily always at the same time)
Receives: Drug: Rituximab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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:

    Measured: at 24 months

Secondary outcomes (8)

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

    Measured: at 30 months

  2. 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.

    Measured: baseline and week 106

  3. 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)

    Measured: at 24 weeks

  4. 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.

    Measured: at 12 or 24 weeks or thereafter

  5. 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

    Measured: at 12 or 24 weeks or thereafter

  6. 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).

    Measured: 12, 24 or 52 weeks

  7. 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.

    Measured: at 12 or 24 weeks or thereafter

  8. Adverse Events (AEs)

    AEs will be evaluated using the NCI CTCAE v4.0

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 May 2015 (estimated)
  2. Study start6 Nov 2015
  3. Primary completion1 Dec 2022
  4. Study completion15 Jul 2023

Why it stopped: The premature termination is based on the decision by the SAKK board on November 14, 2020 due to the lack of further financial support for the follow up period.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
190 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02451111
Sponsor's protocol ID
SAKK 35/14
Other IDs
2015-001487-19, SNCTP000001327, 2015
Status last verified
Mar 2024
First submitted
19 May 2015
Last updated
13 Mar 2024
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ibrutinib and Rituximab in people with Follicular Lymphoma, run by Swiss Cancer Institute at 42 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 13 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 42 sites in Switzerland, Sweden, Denmark, Finland, Norway and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: The premature termination is based on the decision by the SAKK board on November 14, 2020 due to the lack of further financial support for the follow up period.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

CR at 24 months determined by PET/CT scan by the IRR panel (time frame: at 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02451111.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2024.

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