Application of new targeted drugs in relapsed/refractory primary central nervous system lymphoma

Figures & data

Table 1. Summary of prospective trials on new agents in r/r PCNSL.

Clinical trial number	Study design	Intervention	Population	Sample size of r/r PCNSL	ORR (%)	mPFS (mo)	mOS (mo)	Year	Reference
NCT02542514	Multicenter, phase II, no RCT	Ibrutinib	r/r PCNSL and PVRL	52	59	4.8	19.2	2019	Soussain et al (9)
NCT02315326	Single center, phase I, no RCT	Ibrutinib	r/r PCNSL and SCNSL	13	77	4.6	15	2017	Grommes et al (10)
NCT02315326	Single center, phase Ib, no RCT	Ibrutinib + Rituximab + HD-MTX	r/r PCNSL and SCNSL	9	89	9.2	not reached	2019	Grommes et al (13)
JapicCTI-173646	multicenter, phase I/II, no RCT	Tirabrutinib	r/r PCNSL	44	64	2.9	not reached	2021	Narita et al (15)
NCT00942747	multicenter, phase II, no RCT	Temsirolimus	r/r PCNSL	37	54	2.1	3.7	2016	Korfei et al (20)
NCT01956695	multicenter, phase II, no RCT	R2 followed by lenalidomide maintenance	r/r PCNSL and PVRL	45	67	7.8	17.7	2019	Ghesquieres et al (28)
NCT01722305	multicenter, phase I, no RCT	POM + DEX followed by POM maintenance	r/r PCNSL and PVRL	23	48	5.3	not reported	2018	Tun et al (32)

Abbreviations: RCT = randomized clinical trial; HD-MTX = high-dose methotrexate; R2 = lenalidomide + rituximab; POM = pomalidomide; DEX = dexamethasone; r/r = relapsed/refractory; PCNSL = primary central nervous system lymphoma; PVRL = primary vitreoretinal lymphoma; SCNSL = secondary central nervous system lymphoma; ORR = overall response rate; mPFS = median progression free survival; mOS = median overall survival.

Table 2. Selection of ongoing trials evaluating novel therapeutic approaches in R/R PCNSL.

NCT Number	Phase	Number Enrolled	Conditions	Interventions	Allocation	Start Date	Completion Date	Location
BTK inhibitors
NCT02203526	I	93	r/r PCNSL	Ibrutinib + Immunochemotherapy	N/A	2014.08.14	2023.06.15	US
NCT02315326	I, II	109	ND-PCNSL, r/r PCNSL, r/r SCNSL	Ibrutinib ± HD-MTX	Non-Randomized	2014.12	2022.12	US
NCT02542514	II	39	r/r PCNSL	Ibrutinib	N/A	2015.09	2022.01	France
NCT04066920	II	30	r/r PCNSL	IBER followed by ibrutinib maintenance	N/A	2019.10.01	2023.09.30	Korea
NCT04129710	II	120	r/r PCNSL	Ibrutinib versus lenalidomide in combination with MRE-chemotherapy	Randomized	2020.01.01	2025.12.31	China
NCT04548648	II	32	r/r PCNSL, r/r SCNSL	Acalabrutinib	N/A	2020.10.15	2028.12	US
NCT04906902	I, II	49	r/r CNSL	Acalabrutinib	N/A	2021.11	2025.01.31	US
NCT04438044	II	39	r/r PCNSL, r/r SCNSL	ICP-022 (orelabrutinib)	N/A	2019.06.18	2022.12.31	China
NCT05021770	I, II	29	r/r PCNSL	Orelabrutinib + thiotepa	Non-Randomized	2021.12	2024.06	China
NCT04947319	II	44	r/r PCNSL	ONO-4059 (tirabrutinib)	N/A	2021.09.01	2026.07.01	US
NCT03740529	I, II	860	r/r CLL/SLL, r/r NHL	LOXO305 (BTK inhibitor)	Non-Randomized	2018.11.16	2023.05	US
PD-1/PD-L1 antibodies
NCT03255018	II	12	r/r GZL, r/r PCNSL, r/r extranodal DLBCL	Pembrolizumab	N/A	2018.02.15	2023.07.01	US
NCT04070040	II	21	r/r PCNSL	Camrelizumab	N/A	2020.02.13	2022.09.01	China
NCT04457869	II	43	r/r PCNSL, r/r SCNSL	F520	N/A	2020.11.01	2023.01.01	China
PI3K/mTOR inhibitors
NCT04906096	II	25	r/r PCNSL	GDC-0084 (Paxalisib)	N/A	2021.06.01	2024.05.01	US
Other novel agents
NCT01421524	I	271	Advanced solid tumors, NHL or MM	CC-122	Randomized	2011.09.12	2022.08.01	US
NCT03220646	II	78	Recurrent primary brain tumors	Abemaciclib (CDK inhibitor)	Non-Randomized	2017.07.13	2022.07	US
NCT03328078	I, II	96	r/r hematologic malignancies	CA-4948 (IRAK4 inhibitor)	Non-Randomized	2017.12.28	2022.12	US
NCT02952508	II	120	r/r B-cell malignancies	CLR 131 (PDC)	Non-Randomized	2017.07.26	2025.06	US
NCT04089449	I	75	r/r CNSL, Gliomas, Advanced solid tumor	PRT811 (PARP inhibitor)	N/A	2019.11.06	2022.12	US
NCT04807881	I	75	r/r BCL	Keynatinib (EGFR-TKI)	N/A	2020.09.24	2023.04.10	China
BTK inhibitor + PD-1/PD-L1 antibody
NCT03770416	II	40	r/r CNSL	Ibrutinib + Nivolumab	Non-Randomized	2019.02.15	2023.06.15	US
NCT04421560	I, II	37	r/r PCNSL	Rituximab, Ibrutinib, Pembrolizumab	N/A	2020.08.01	2024.03.05	US
NCT04899427	II	32	r/r PCNSL	Orelabrutinib + PD-1 inhibitor	N/A	2021.03.24	2023.10.24	China
NCT04961515	I, II	48	r/r PCNSL	Orelabrutinib + Sintilimab	Non-Randomized	2021.06.01	2026.12.31	China
NCT04688151	I	22	r/r PCNSL	RAD (Rituximab, acalabrutinib, durvalumab)	Non-Randomized	2021.02.01	2025.12.31	Taiwan
NCT04462328	I	21	r/r PCNSL r/r SCNSL	Acalabrutinib + Durvalumab	Non-Randomized	2021.04.29	2026.11.30	US
BTK inhibitor + PI3K/mTOR inhibitor
NCT03581942	I, II	45	r/r PCNSL	Ibrutinib + Copanlisib	N/A	2018.08.23	2023.07	US
BTK inhibitor + Immunomodulator
NCT03703167	I	40	r/r PCNSL, r/r SCNSL	Ibrutinib with rituximab and lenalidomide	N/A	2019.01.22	2022.11	US
NCT04938297	II	100	ND-PCNSL, r/r PCNSL, r/r SCNSL	ZR2 (Rituximab, zanubrutinib, lenalidomide)	Non-Randomized	2021.05.26	2025.12.31	China
CAR-T
NCT04134117	I	6	r/r PCNSL	Tisagenlecleucel	N/A	2019.12.11	2022.11	US
NCT04608487	I	18	r/r CNSL	Axi-cel	N/A	2020.12.04	2023.09.01	US
NCT04443829	I	12	r/r PCNSL	CD19 CAR-T	N/A	2021.03.23	2032.12	UK
NCT03484702	II	116	r/r aggressive BCL	JCAR017	N/A	2018.06.05	2024.03.04	Finland
NCT04464200	I	60	r/r B-cell cancers	19(T2)28z1xx CAR T cells	N/A	2020.07.06	2023.07	US

Abbreviations: r/r = relapsed/refractory; PCNSL = primary central nervous system lymphoma; ND = newly-diagnosed; SCNSL = secondary central nervous system lymphoma; HD-MTX = high-dose methotrexate; IBER = ibrutinib + rituximab + ifosfamide + etoposide; MRE = methotrexate + rituximab + etoposide; CLL/SLL = chronic lymphocytic leukemia/small lymphocytic leukemia; NHL = non-Hodgkin‘s lymphoma; GZL = gray zone lymphoma; DLBCL = diffuse large B cell lymphoma; MM = multiple myeloma; CDK = cyclin-dependent kinases; IRAK4 = interleukin-1 receptor-associated kinase 4; PDC = peptide drug conjugate; CNSL = central nervous system lymphoma; PARP = poly adenosine diphosphate ribose polymerase; BCL = B-cell lymphoma; EGFR-TKI = epidermal growth factor receptor tyrosine kinase inhibitor; CAR-T = chimeric antigen receptor T-cell immunotherapy; N/A = not applicable.