Table 2.

Selected trials designed to overcome resistance or intolerance to targeted therapies in CLL

ClinicalTrials.gov ID	Resistance	Treatment	Target	Strategy	Study phase	Comment
NCT03513562	Ibrutinib	Ibrutinib + venetoclax	BTK, BCL-2	Combination	2	CLL with genetic mutations after ibrutinib treatment
NCT03943342	Ibrutinib	Ibrutinib + venetoclax	BTK, BCL-2	Combination	2	CLL resistant to ibrutinib
NCT03128879	Ibrutinib	Ibrutinib + venetoclax	BTK, BCL-2	Combination	2	CLL with BTK mutation
NCT04209621	Ibrutinib	Ibrutinib + duvelisib	BTK, PI3K	Combination	2	BTK and/or PLCG2 mutations and/or progressive CLL
NCT03422393	Ibrutinib	Ibrutinib + venetoclax	BTK, BCL-2	Combination	1	CLL progressing on single agent ibrutinib
NCT03370185	BTKi	Duvelisib	PI3K	Sequencing	2	CLL relapsed/refractory to BTKi, or discontinued due to toxicity
NCT04149821	BTKi or BCL-2i	Umbralisib + ublituximab	PI3K, CD20	Sequencing	2	CLL progressed on a BTKi or BCL-2i
NCT03037645	SoC including BTKi	Vecabrutinib (SNS-062)	BTK (reversible)	Next-generation therapy	1/2	CLL failed standard of care therapies including a BTKi
NCT03740529	SoC	LOXO-305 ± venetoclax, rituximab, R-CHOP	BTK (reversible), BCL-2, CIT	Next-generation therapy	1/2	CLL failed or intolerant to standard of care
NCT02968563	BCL-2i, BTKi, PI3Ki, SYKi, or obinutuzumab	Tirabrutinib ± idelalisib ± obinutuzumab	BTK (irreversible), PI3K, CD20	Next-generation therapy	2	Progression on treatment with any BTKi, SYKi, PI3Ki, BCL-2i, or obinutuzumab

CIT, chemoimmunotherapy; R-CHOP, rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone; SoC, standard of care; SYK, spleen tyrosine kinase.