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

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).