Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma

Abstract

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

“…Of further interest, ibrutinib has been reported to cross the blood‐brain barrier and has recently shown efficacy in CNS lymphomas and in MCL involving the CNS . These results have potential to impact future therapies for high‐risk MCL patients who have CNS involvement or at high risk of CNS involvement.…”

Germinal center‐derived lymphomas: The darkest side of humoral immunity

“…Adding BTK inhibitor to the standard DLBCL chemoimmunotherapy R-CHOP regimen in non-GCB-DLBCL did not improve survival 202 but other combinations might prove to be more beneficial. BTK inhibition has proven quite successful when used as a single agent in PCNSL (primary central nervous system DLBCL) and secondary CNSL, [203][204][205] with clinical response seen in 78% of CNS lymphoma patients in a phase II study. 204 An Ibrutinib/Methotrexate/ Rituximab combination has shown manageable toxicity and promising results in relapsed/refractory CNS lymphomas with 80% clinical response rate in a phase Ib trial.…”

“…BTK inhibition has proven quite successful when used as a single agent in PCNSL (primary central nervous system DLBCL) and secondary CNSL, [203][204][205] with clinical response seen in 78% of CNS lymphoma patients in a phase II study. 204 An Ibrutinib/Methotrexate/ Rituximab combination has shown manageable toxicity and promising results in relapsed/refractory CNS lymphomas with 80% clinical response rate in a phase Ib trial. 204 Targeting further downstream components of the BCR pathway is desirable in order to bypass BTK inhibitor resistance conferred by mutations of genes such as PLCγ, CARD11, and BCL10.…”

“…204 An Ibrutinib/Methotrexate/ Rituximab combination has shown manageable toxicity and promising results in relapsed/refractory CNS lymphomas with 80% clinical response rate in a phase Ib trial. 204 Targeting further downstream components of the BCR pathway is desirable in order to bypass BTK inhibitor resistance conferred by mutations of genes such as PLCγ, CARD11, and BCL10. Along these lines compounds that target the MALT1 paracaspase are highly effecting in suppressing ABC-DLBCLs in vitro and in vivo.…”

Advances in targeted therapy for malignant lymphoma

“…Moreover, the sequential combination of ibrutinib with high-dose methotrexate and rituximab was studied in patients with primary central nervous system lymphoma (PCNSL) (NCT02315326). 203 Acalabrutinib (ACP-196) is a BTK inhibitor that has been proven to have a more enhanced efficacy than ibrutinib in canine studies. 204 A phase 2 study (NCT02213926) reported an ORR of 81% (CR 40%) in relapsed or refractory MCL.…”