Phase Ib Trial with Dose Expansion of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab and Lenalidomide in Patients with Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL) and Refractory/Recurrent Secondary Central Nervous System Lymphoma (SCNSL)

BACKGROUND: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single-agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). We hypothesize that combing ibrutinib with the immunomodulatory imide lenalidomide and theanti-CD20 antibody rituximab would be adding clinical efficacy. In this phase 1b trial, we investigate the toxicity of ibrutinib in combination with rituximab and lenalidomide in r/r PCNSL/SCNSL.

METHODS: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. Enrollment followed the 3+3 design. Ibrutinib was dosed at 560mg daily (dose level 1) and 840mg (level 2, 3, 4); lenalidomide was dosed at 10mg daily (day 1-21) (level 1, 2), 15mg daily (day 1-21) (level 3) and 20mg daily (day 1-21) (level 4); rituximab was dosed at 500mg/m2 (all dose levels). Rituximab was given for 6 cycles, lenalidomide for 12 cycles, and ibrutinib ongoing.

RESULTS: Fifteen patients have been enrolled; 3 at dose level 1-3 and 6 at level 4. Median age was 69 years (range 56-82); 4 were women. Median ECOG was 1 (0: 5, 1: 7, 2: 3). Eleven had r/r PCNSL. Eleven had recurrent parenchymal disease; two had additional cerebrospinal fluid (CSF) involvement; two had both. Nine patients had recurrent and 6 refractory disease. No DLT occurred. One grade 4 lymphopenia was observed. The following grade 3 events occurred: rash (in 3 patients); lymphopenia (in 2); AST, ALT, lung infection, and elevated aPTT (in 1). The most common adverse events were thrombocytopenia, lymphopenia, and rash. No Aspergillosis infection was observed. After a median follow-up of 6.9 months, 14/15 were evaluated for response with 13/15 (73%) showing a response: 4 CR, 7 PR, and 2 SD, 1 PD. Median PFS was 3.03 months; not yet reached for Dose level 4 (only 1/6 has developed progression with a median follow up of 5 months).

CONCLUSION: Patients with CNS lymphoma tolerate the combination of rituximab, lenalidomide and ibrutinib well. No dose limiting toxicities were observed. No Aspergillosis infection occurred with this combination regimen. Continued enrollment is ongoing.