Phase 1b Study of Tirabrutinib in Combination With Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia
Mené sur 53 patients atteints d'une leucémie lymphocytaire chronique réfractaire ou récidivante, cet essai de phase IB évalue la dose maximale tolérée et l'efficacité, du point de vue du taux de réponse, du tirabrutinib (un inhibiteur de BTK) dispensé seul ou en combinaison avec l'idélalisib (un inhibiteur de PI3Kdelta) ou avec l'entosplétinib (un inhibiteur de SYK)
Purpose: Bruton's tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase 1b, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib (TIRA) alone, in combination with the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib (IDELA), or with the spleen tyrosine kinase (SYK) inhibitor entospletinib (ENTO) in patients with relapsed/refractory CLL. Experimental Design: Patients received either TIRA monotherapy (80 mg QD) or TIRA 20 mg to 150 mg QD in combination with either IDELA (50 mg BID or 100 mg QD) or ENTO (200 mg or 400 mg QD). Results: Fifty-three patients were included. Systemic TIRA exposure was comparable between monotherapy and combination therapy. No maximum tolerated dose was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving TIRA, TIRA/IDELA, and TIRA/ENTO, respectively. As of February 21, 2019, 46/53 patients continue to receive treatment on study. Conclusions: TIRA in combination with IDELA or ENTO was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over TIRA alone. This trial is registered at
www.clinicaltrials.gov
(NCT02457598).