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

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

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

Results: 25 patients were enrolled (3 each into dose level 1-3; 6 into level 4; 10 into expansion cohort at level 4). Median age was 67 years (range 41-85) and median ECOG 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 median follow-up, 20/25 (80%) showed a response with a median time to best response 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=0.003).

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