Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial

Abstract

BackgroundTreatment of chronic lymphocytic leukaemia (CLL) has seen a substantial improvement over the last few years. Combination immunochemotherapy, such as fludarabine, cyclophosphamide and rituximab (FCR), is now standard first-line therapy. However, the majority of patients relapse and require further therapy, and so new, effective, targeted therapies that improve remission rates, reduce relapses, and have fewer side effects, are required. The FLAIR trial will assess whether ibrutinib plus rituximab (IR) is superior to FCR in terms of progression-free survival (PFS).Methods/designFLAIR is a phase III, multicentre, randomised, controlled, open, parallel-group trial in patients with previously untreated CLL. A total of 754 participants will be randomised on a 1:1 basis to receive standard therapy with FCR or IR. Participants randomised to FCR will receive a maximum of six 28-day treatment cycles. Participants randomised to IR will receive six 28-day cycles of rituximab, and ibrutinib taken daily for 6 years until minimal residual disease (MRD) negativity has been recorded for the same amount of time as it took to become MRD negative, or until disease progression. The primary endpoint is PFS according to the International Workshop on CLL (IWCLL) criteria. Secondary endpoints include: overall survival; proportion of participants with undetectable MRD; response to therapy by IWCLL criteria; safety and toxicity; health-related quality of life (QoL); and cost-effectiveness.DiscussionThe trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of PFS, and whether toxicity rates are favourable.Trial registration ISRCTN01844152. Registered on 8 August 2014, EudraCT number 2013-001944-76. Registered on 26 April 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-2138-6) contains supplementary material, which is available to authorized users.

Ibrutinib induces chromatin reorganisation of chronic lymphocytic leukaemia cells

“…Ibrutinib (PCI-32765), a specific and irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK), is a small molecule orally administered, providing a selective and irreversible inhibition of BTK. In extensive studies, Ibrutinib has shown extremely promising results in front-line treatment as well as in relapsed/refractory (RR) CLLs 5,6 and is now tested in combination with other molecules 7 . However, cases of drug resistance have emerged 8,9 .…”

Past, Present, and Future of Rituximab—The World’s First Oncology Monoclonal Antibody Therapy

“…In CLL patients who are young and fit and lack deletion of 17p or TP53, current treatment guidelines recommend chemotherapy, commonly fludarabine, cyclophosphamide in combination with rituximab (FCR) as initial treatment based on the proven effectiveness of rituximab from several clinical trials ( 70 ). A recent Canadian study confirmed the tangible benefits in CLL by evaluating patients treated in the pre- and post-rituximab era ( 71 ).…”

“…The currently ongoing FLAIR phase III trial includes 754 CLL patients given either the current standard of care FCR, ibrutinib plus rituximab, ibrutinib plus venetoclax, or ibrutinib alone, potentially eliminating the need for more harmful chemotherapeutics in favor of more targeted therapeutics as the new standard of care ( 70 ). This study should also assess the benefit of the addition of rituximab to small molecule targeted therapies (in this case ibrutinib), which has been relatively understudied.…”

<p>The expanding role of venetoclax in chronic lymphocytic leukemia and small lymphocytic lymphoma</p>

“…The FLAIR trial is randomizing untreated patients with CLL/ SLL in 1:1:1:1 ratio to FCR immunochemotherapy or three versions of ibrutinib therapy: ibrutinib monotherapy, IR, or VI. 51 Ibrutinib and venetoclax therapy can be continued for up to 6 years or discontinued if uMRD is attained. Both of these trials will be the first opportunity to compare VI and other venetoclax-based or ibrutinib-based novel chemotherapy free regimens to our standard chemotherapy strategies in the frontline setting.…”