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|Ref Type||Journal Article|
|Authors||Danilov AV, Herbaux C, Walter HS, Hillmen P, Rule SA, Kio EA, Karlin L, Dyer MJS, Mitra SS, Yi PC, Humeniuk R, Huang X, Zhou Z, Bhargava P, Jürgensmeier JM, Fegan CD|
|Title||Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2020 Jun 15|
|Abstract Text||Bruton 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 Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL.Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day).Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD 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 tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study.Tirabrutinib in combination with idelalisib or entospletinib 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 tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Entospletinib||GS-9973|GS 9973|GS9973||SYK Inhibitor 13||Entospletinib (GS-9973) is a selective spleen tyrosine kinase (Syk) inhibitor, which in turn inhibits B-cell receptor signaling, leading to suppression of cell migration and inhibition of survival (PMID: 24779514, PMID: 32156743).|
|Tirabrutinib||ONO-GS-4059|ONO-WG-307|ONO-4059||BTK inhibitor 22||Tirabrutinib (ONO-4059) inhibits Bruton's Tyrosine Kinase (BTK), which leads to decreased B-cell proliferation and differentiation, and may have antitumor activity in B-cell malignancies (PMID: 23958373, PMID: 27776353, PMID: 32156743).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||chronic lymphocytic leukemia||not applicable||Tirabrutinib||Phase I||Actionable||In a Phase Ib trial, Tirabrutinib (ONO-4059) treatment was well tolerated, resulted in a overall response rate of 83% (24/29) with complete response in 7% (2/29) of patients with chronic lymphocytic leukemia (PMID: 32156743; NCT02457598).||32156743|
|Unknown unknown||chronic lymphocytic leukemia||not applicable||Idelalisib + Tirabrutinib||Phase I||Actionable||In a Phase Ib trial, Tirabrutinib (ONO-4059) and Zydelig (idelalisib) combination treatment was well tolerated, resulted in a overall response rate of 93% (13/14) with complete response in 7% (1/14) of patients with chronic lymphocytic leukemia (PMID: 32156743; NCT02457598).||32156743|
|Unknown unknown||chronic lymphocytic leukemia||not applicable||Entospletinib + Tirabrutinib||Phase I||Actionable||In a Phase Ib trial, Tirabrutinib (ONO-4059) and Entospletinib combination treatment was well tolerated, resulted in a overall response rate of 100% (10/10) with complete response in 10% (1/10) of patients with chronic lymphocytic leukemia (PMID: 32156743; NCT02457598).||32156743|