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Clinical Trial
. 2025 Sep 17;27(8):2107-2116.
doi: 10.1093/neuonc/noaf104.

Phase Ib study with expansion of ibrutinib, lenalidomide, and rituximab in patients with relapsed/refractory central nervous system lymphoma

Lauren R Schaff  1   2 , Anna F Piotrowski  1   2 , Elena Pentsova  1   2 , Igor T Gavrilovic  1   2 , Andrew Lin  1   2 , Thomas J Kaley  1   2 , Venissala Wongchai  2 , Laleh Emadi-Paramkouhi  2 , Juli Madzsar  2 , Lillian Quinn  2 , Ashley Gonzalez  2 , Laura Breakey  2 , Sarah S Tang  2 , Joe S Mendez  3   2 , Rachna Malani  3   2 , Craig Nolan  1   2 , Vaios Hatzoglou  4 , Robert J Young  4 , Lisa M DeAngelis  1   2 , Anne S Reiner  5 , Katherine S Panageas  5 , Jasmine H Francis  3 , Ingo K Mellinghoff  1   2 , Christian Grommes  1   2
Affiliations
Clinical Trial

Phase Ib study with expansion of ibrutinib, lenalidomide, and rituximab in patients with relapsed/refractory central nervous system lymphoma

Lauren R Schaff et al. Neuro Oncol. .

Abstract

Background: Treatment options for recurrent/refractory central nervous system (CNS) lymphoma are limited but Bruton's tyrosine kinase inhibitor ibrutinib has shown promise. To increase efficacy and reduce resistance, ibrutinib was combined with lenalidomide in a preclinical study and rituximab (R2I) in a phase Ib trial with expansion.

Methods: Ibrutinib 560 mg (dose level 1) or 840 mg (levels 2-4) was administered daily; lenalidomide was dosed on days 1-21 at 10 mg (level 1 + 2), 15 mg (level 3), or 20 mg (level 4) daily; rituximab 500 mg/m2 was administered every 28 days. Rituximab was given for 6 cycles, lenalidomide for 12 cycles, and ibrutinib ongoing.

Results: 25 patients were enrolled (3 each into dose levels 1-3; 6 into level 4; and 10 into the expansion cohort at level 4). The median age was 67 years (range 41-85) and the median Eastern Cooperative Oncology Group 1 (range 0-2). Patients had a median of 2 prior regimens (range 1-5). Common adverse events were thrombocytopenia, rash, and lymphopenia. No aspergillosis or grade 5 toxicities were observed. After 12.8 months of median follow-up, 20/25 (80%) showed a response with a median time to best response of 60 days (range, 25-615). Median progression-free survival (PFS) was 4.3 months (95% CI: 2.4-not reached) with a PFS12m of 37% (95% CI: 22%-63%). Median overall survival has not been reached. Patients with rash during treatment had improved PFS (HR: 0.17, 95% CI: 0.05-0.55, P-value = .003).

Conclusions: R2I was tolerated well with high response rates and a short time to best respond. Median PFS was limited but 1/3 of patients had durable responses >12 months. This trial was registered at www.clinicaltrials.gov (NCT03703167).

Keywords: CNS lymphoma; central nervous system lymphoma; ibrutinib; lenalidomide.

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Conflict of interest statement

L.R.S: Patent pending: BTG; Scientific Advisory Board: BTG, Consultation: ONO, Servier. A.L: Grant to support clinical trials to the institution: Bristol Myers Squibb. T.J.K: Consultation: Servier. R.J.Y: Equity:Agios; Consultation: Guerbet, ICON plc, NordicNeuroLab, Olea Medical, RadMD, Servier, Turing Medical. L.M.D: Advisory board: of Break Through Cancer; Scientific Advisory Board of Starlight Therapeutics. I.K.M: Consultation: Servier, Tango Therapeutics, Erasca, Agios, Roche, Global Coalition for Adaptive Research; Research grants from Eli Lilly and Company, Puma Biotechnology, and General Electric outside the submitted work. C.G: Patent pending: BTG; Grant to support this study to the institution: Pharmacyclics; Consultation: ONO, Roche, BTG, Curis; Travel support: Ono; Grants to support prior and ongoing clinical trials to the institution: Bayer, Bristol Myers Squibb.

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