Ibrutinib, an inhibitor of Bruton´s tyrosine kinase (BTK) is approved in CLL as continuous, daily administration of 420 mg orally until progression. Ibrutinib drug costs in health care are rapidly increasing and are difficult to predict, as long-term follow up analyses have shown that many patients remain on therapy for several years, in some cases even many years. It has been observed that patients who stop ibrutinib due to side effects may often remain with continued CLL disease control i.e. in stable partial remission even when off ibrutinib therapy. There are also emerging data on mutations within BTK, with loss of efficacy of ibrutinib, during long-term continuous administration. These observations raise the question whether alternative dosing strategies may be feasible. This pilot study will explore intermittent and repeated dosing of ibrutinib, until alternative therapy is required due to resistance or intolerance to ibrutinib. An "ON-OFF" dosing strategy will be applied, where advanced-phase CLL patients who have received at least 6 months of ibrutinib and who have achieved a stable PR will stop ibrutinib and be followed off therapy until clinical progression, at which ibrutinib will be re-instituted. Such "ON-OFF" ibrutinib cycles may be repeated until non-tolerability or resistance, or need of continuous dosing of ibrutinib (i.e. early progression when off the drug). If successful, the study will indicate a way forward towards reducing ibrutinib drug costs in health care without affecting long-term disease control, possibly also with fewer ibrutinib-related side effects due to a lower cumulative dose of ibrutinib. Long-term effects on potential mutations within BTK and its downstream signaling molecules will also be analysed.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Ibrutinib will be stopped at inclusion in the and the patient will be followed OFF therapy. At clinical progress, ibrutinib will be restarted (ON period) at the same standard dose as used at inclusion. When the patient achieve at least partial response again, a new OFF period is started, and so on.
St Olavs Hospital
Trondheim, Norway
RECRUITINGFalu lasarett
Falun, Dalarna County, Sweden
RECRUITINGGävle Hospital
Gävle, Gävleborg County, Sweden
RECRUITINGSkåne University Hospital
Lund, Skåne County, Sweden
NOT_YET_RECRUITINGSahlgrenska University Hospital
Gothenburg, Sweden
NOT_YET_RECRUITINGÖrebro University Hospital
Örebro, Sweden
RECRUITINGKarolinska University Hospital
Stockholm, Sweden
RECRUITINGNorrland's University Hospital
Umeå, Sweden
NOT_YET_RECRUITINGAkademiska hospital
Uppsala, Sweden
RECRUITINGSafety measured as type, frequency and severity of adverse events.
Type, frequency and severity of adverse events and relationship to intermittent ibrutinib dosing.
Time frame: Through study completion, 1-24 months.
Overall response at each treatment cycle.
Response when re-starting ibrutinib, at each cycle.
Time frame: Through study completion, 1-24 months.
Time to PR and PR-L at each cycle.
Time to partial response (PR) and partial response with persistent lymphocytosis (PR-L) when re-starting ibrutinib, at each cycle.
Time frame: Through study completion, 1-24 months.
Time to stop until restart of ibrutinib due to progress
Time from the patient going off ibrutinib until it has to be re-started due to progressive, for each cycle.disease (PD), at each cycle.
Time frame: Through study completion, 1-24 months.
Number of ibrutinib treatment cycles and OFF therapy periods.
The number of cycles each patient stop and re-start ibrutinib.
Time frame: Through study completion, 1-24 months.
Cumulative dose of ibrutinib.
The cumulative dose of ibrutinib for each patient.
Time frame: Through study completion, 1-24 months.
Overall survival.
Overall survival.
Time frame: Through study completion, 1-24 months.
Risk of early rebound phenomenon.
Observation of early rebound phenomemon at each re-start of ibrutinib.
Time frame: Through study completion, 1-24 months.
Time to need of alternative treatment.
Time to need of alternative treatment.
Time frame: Through study completion, 1-24 months.
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