Ibrutinib is highly efficacious and used at 420 mg/d for treatment of
chronic lymphocytic leukemia (CLL). We previously demonstrated a decline in
Bruton's tyrosine kinase (BTK)
protein levels in CLL cells after 1 cycle of
ibrutinib, suggesting
ibrutinib dose could be lowered after the first cycle without loss of
biological effect. To test this postulate, a pilot study (NCT02801578) was designed to systematically reduce
ibrutinib dosing within the same patient with CLL over the course of three 28-day cycles. After an initial cycle of 420 mg/d, the dose was reduced to 280 mg/d in cycle 2, and then to 140 mg/d in cycle 3. Eleven patients began study treatment, and 9 completed the 3 cycles. Plasma and intracellular pharmacokinetics (PK), BTK occupancy, and pharmacodynamic (PD) response at different doses of
ibrutinib were compared. Plasma and intracellular levels of
ibrutinib were dose-dependent, and even the lowest dose was sufficient to occupy, on average, more than 95% of BTK
protein. In concert, BTK downstream signaling inhibition was maintained with 140 mg/d
ibrutinib in cycle 3, and there were comparable reductions in total and phospho-BTK (Tyr223)
protein levels across 3 cycles. Reductions of plasma
chemokine CCL3 and CCL4 levels, considered to be
biomarkers of
ibrutinib response, were similar during the 3 cycles. These PK/PD data demonstrate that after 1 cycle of
ibrutinib at the standard 420 mg/d dose, the dose can be reduced without losing
biological activity. Clinical efficacy of lower doses needs to be systematically evaluated. Such
dose reductions would lower drug cost, lessen untoward toxicity, and facilitate rationale-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT02801578.