Phase Ib/II Trial of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab and Lenalidomide in Refractory/Recurrent Primary (PCNSL) and 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 the anti-CD20 antibody rituximab would be adding clinical efficacy. In this phase Ib/II trial, we investigate the toxicity and efficacy of ibrutinib in combination with rituximab and lenalidomide in r/r PCNSL/SCNSL.

METHODS: Eligible patients had r/r PCNSL/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. Ten additional patients received treatment at the MTD defined in the phase Ib portion.

RESULTS: Fifteen patients were enrolled into the phase Ib portion and 10 were treated at the MTD of rituximab at 500 mg/m2, lenalidomide at 20mg daily on day 1-21, and ibrutinib at 840mg daily. Median age was 67 years (range 41-85); 9 were women. Median ECOG was 1 (0: 10, 1: 10, 2: 5), 18 had r/r PCNSL. Ten had parenchymal disease; 12 had brain and cerebrospinal fluid (CSF) involvement; one had CSF only involvement. Eleven patients had recurrent and 14 refractory disease with a median of 2 prior recurrence (range 1-5; 7 had prior ASCT, 2 prior WBRT). No DLT occurred in the phase Ib cohort. No grade 5 toxicity was observed. One grade 4 lymphopenia and 2 grade 4 neutropenias were observed. No Aspergillosis infection was observed. The most common adverse events were thrombocytopenia, rash, and lymphopenia. After a median follow-up of 27 months, all patients were evaluated for response with 20/25 (80%) showing a response: 9 CR, 11 PR, and 1 SD, 4 PD. Median time to best response was 60 days. Ten patients were on corticosteroids at time of enrollment. Of the 9 CRs only one was on corticosteroids. Median PFS was 4.3 months with a PFS6m of 42% and PFS12m of 37%. Median OS has not been reached yet. Patients with recurrent disease had a better median PFS (not reached vs. 2.3 months in refractory cases), those with prior ASCT had a poorer median PFS (1.7 vs. 9.6 months in those without ASCT). Patients developing a rash also had a better median PFS (undefined vs. 2.3 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. Response rate was high with a short time to best response in a highly pretreated population with 56% refractory patients. Even though median PFS was limited, a third of patients had a durable response beyond 12 months. Particularly those developing a rash and with recurrent disease without prior ASCT benefitted from the trial treatment.

Grommes:Scripps Conference Services & CME: Other: provision of services; Ono Pharma: Other: provision of services; Kite Pharmaceuticals: Other: provision of services; Ampressa Therapeutics, Inc: Other: provision of services; BTG International: Other: provision of services. Schaff:BTG International: Other: Intellectual property rights; Debiopharm: Other: provision of services.