Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study
Authors: Langerbeins Petra , Bahlo Jasmin , Rhein Christina , Cramer Paula , Fink Anna-Maria , Pflug Natali , von Tresckow Julia , Stilgenbauer Stephan , Kreuzer Karl-Anton , Eckart Michael J. , Vehling-Kaiser Ursula , Schlag Rudolf , Balser Christina , Müller Lothar , Wendtner Clemens-Martin , Fischer Kirsten , Eichhorst Barbara , Hallek Michael 
Published: October 2019

Abstract
Introduction
Observation (watch and wait) is the standard of care for patients with asymptomatic early stage CLL. Prognostic scores can be used to predict the outcome for high-risk subgroups that have rapid disease progression and poor survival. So far early treatment intervention failed to improve survival. However with development of novel targeted drugs treatment of high-risk CLL has improved. Thus, the risk-stratified management of early stage CLL needs to be re-evaluated.
The CLL12-trial is the first prospective, placebo-controlled, double-blind, phase 3 trial investigating whether ibrutinib improves event-free survival (EFS) and therefore time to therapy in early stage CLL with risk of disease progression defined by a comprehensive prognostic score (Langerbeins et al, Future Oncol, 2015).
Methods
In this ongoing trial subjects with confirmed asymptomatic Binet stage A CLL are risk stratified according to the CLL-score (Pflug et al, Blood, 2014). Whereas low-risk patients are being observed (watch & wait), intermediate to very high-risk patients are randomized 1:1 to receive either treatment with ibrutinib at a daily dose of 420mg or placebo. A cycle is defined as 28 calendar days. Primary endpoint is EFS defined as the time between randomization until progressive disease, subsequent CLL-treatment or death. The trial is registered at www.clinicialtrialsregister.eu(EudraCT 2013-003211-22).
Results
At submission of the abstract, a total of 327 patients have been screened. Main reasons for screening failure (N=65) were violation of in-/exclusion criteria (N=32), withdrawal of consent (N=24) and incomplete screening (N=9). Patients were stratified using the prognostic score as follows: low (score 0-2, N=82), intermediate (score 3-5, N=125), high (score 6-10, N=39) and very high risk (score 11-14, N=6). Low-risk patients were allocated to the observational arm. The remaining 170 patients were randomized 1:1 to the experimental arm. Thus far, a total of 587 cycles have been administered with a median treatment duration of 4 cycles per patient. 46 patients have stopped the treatment prematurely. Reasons for early discontinuation were refusal of further treatment (N=26), toxicity (N=10), disease progression (N=6), concomitant use of oral anticoagulants (N=3) and lung cancer (N=1).
26 serious adverse events (SAE) including two suspected unexpected serious adverse reactions (SUSAR) have been reported for both treatment arms (placebo vs. ibrutinib): cardiac disorders (N=6), infections (N=9), nervous system disorders (N=2), vascular disorders (N=2), musculoskeletal disorders (N=2), acute renal failure (N=1), vertigo (N=1), sigmadiverticulitis (N=1), sacrumfracture (N=1), and small cell lung cancer (N=1). 15 of the reported SAE's were deemed related to the study medication.
The first SUSAR was a non-ST elevation myocardial infarction in an 82-year old male patient with high comorbidity score (CIRS=6) including known coronary heart disease, hypertension, diabetes mellitus and obesity. The second SUSAR was cerebral seizure secondary to subdural bleeding reported in a 78-year old male patient with high CIRS (N=12) and concomitant use of rivaroxaban. To minimize bleeding risk the study was amended to exclude patients using novel, oral anticoagulants. Subjects receiving direct Xa-inhibitors either changed the anticoagulant or stopped the experimental treatment.
Conclusion
Clinical observation has been the standard of care for early stage CLL ever since. This is the first safety report of a recruiting placebo-controlled phase III trial investigating if targeted treatment with ibrutinib delays time to first therapy in early stage CLL patients. SAE's are consistent with those previously reported for ibrutinib. Concomitant use of oral anticoagulants is prohibited due to an increased risk of bleeding. This may be seen differently in trials where patients already fulfill treatment criteria. Updated safety data will be presented at the meeting. Data from randomized first-line trials in advanced CLL suggests administering the most efficacious treatment upfront to achieve longterm-remissions and prolongation of survival. Efficacy data of the CLL12 trial will be available in 2016 and will hopefully answer this question for early stage patients and guide future management of this subgroup.

Disclosures
Langerbeins: Mundipharma: Honoraria, Other: travel grants, Research Funding; Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; Janssen: Honoraria, Other: travel grants, Research Funding. Off Label Use: Ibrutinib in early stage Binet A CLL. Rhein:Janssen: Other: travel grants. Cramer:Astellas: Other: Travel grant; Gilead: Other: Travel grant, Research Funding; Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau; Glaxo Smith Klein/Novartis: Research Funding; Mundipharma: Other: Travel grant. Fink:Roche: Honoraria, Other: travel grant. Pflug:Celgene: Other: Travel grant. von Tresckow:Celgene: Other: travel grants; Janssen-Cilag: Honoraria, Research Funding; Hoffman-LaRoche: Other: travel grants, Research Funding. Stilgenbauer:AbbVie: Consultancy, Other: travel grants, Research Funding; Amgen: Consultancy, Other: travel grants, Research Funding; Boehringer-Ingelheim: Consultancy, Other: travel grants, Research Funding; Celgene: Consultancy, Other: travel grants, Research Funding; Hoffman-LaRoche: Consultancy, Honoraria, Other: travel grants, Research Funding; Genentech: Consultancy, Other: travel grants, Research Funding; Genzyme: Consultancy, Other: travel grants, Research Funding; Gilead: Consultancy, Other: travel grants, Research Funding; GlaxoSmithKline: Consultancy, Other: travel grants, Research Funding; Janssen: Consultancy, Other: travel grants, Research Funding; Mundipharma: Consultancy, Other: travel grants, Research Funding. Eckart:Gilead: Honoraria; Roche: Other: travel grant. Balser:Iomedico: Other: travel grant; Janssen: Consultancy; Roche: Other: travel grant. Wendtner:Celege: Consultancy, Other: Travel grants, Research Funding; Mundipharma: Consultancy, Other: travel grants, Research Funding; Janssen-Cilag: Consultancy, Other: travel grants, Research Funding; Glaxo-SmithKline: Consultancy, Other: travel grants, Research Funding; Gilead: Consultancy, Other: travel grants, Research Funding; Genentech: Consultancy, Other: travel grants, Research Funding; Hoffmann-LaRoche: Consultancy, Other: travel grants, Research Funding; AbbVie: Consultancy, Other: travel grants, Research Funding; Pharmacyclics: Consultancy, Other: travel grants, Research Funding. Fischer:Roche: Other: Travel Grants. Eichhorst:AbbVie: Consultancy, Other: travel support, Research Funding; Celgene: Consultancy, Other: travel grant, Research Funding; Hoffman-LaRoche: Consultancy, Other: travel grant, Research Funding; Gilead: Consultancy, Other: travel grant, Research Funding; Janssen: Consultancy, Other: travel grant, Research Funding; Mundipharma: Consultancy, Other: travel grant, Research Funding. Hallek:Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Board; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding.