Phase I Study of Dose-Adjusted-Teddi-R with Ibrutinib in Untreated and Relapsed/Refractory Primary CNS Lymphoma

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare type of diffuse large B-cell lymphoma (DLBCL). It closely resembles activated B-cell (ABC) DLBCL and most cases have B cell receptor (BCR) and MyD88 mutations. Ibrutinib is an inhibitor of BTK that targets BCR signaling and is active in patients with relapsed/refractory (R/R) ABC DLBCL.

Methods: Ibrutinib was incorporated into a novel regimen called DA-TEDDI-R (temozolomide, etoposide, doxil, dexamethasone, ibrutinib and rituximab) (with intraventricular cytarabine). DA-TEDDI-R was designed around therapeutic principles for systemic DLBCL and CNS penetration. Methotrexate was excluded due to potential antagonism with ibrutinib based on preliminary in vitro experiments. Untreated or R/R PCNSL patients were eligible and received ibrutinib in cohorts (560-1120 mg/day PO) for 14-days in a "window" prior to cycle 1 of DA-TEDDI-R (with pre and post-brain MRI/FDG-PET), followed by DA-TEDDI-R with ibrutinib (days 1-10) q21 days x 6. Plasma and CSF PKs of ibrutinib and its metabolite PCI-45227 were analyzed. CSF penetration (AUC_CSF: AUC_PLASMA) was corrected for human plasma protein binding: parent: 97.3%, metabolite: 91%. CSF PKs of TEDDI drugs and molecular analysis of FFPE biopsies are ongoing.

Results: Eleven patients have enrolled; 6 were R/R (median 3 (1-5) prior treatments) and 5 were previously untreated. Eleven completed the ibrutinib window and 5 patients completed and 2 remain on DA-TEDDI-R; Ibrutinib dosing was 560 mg in patients 1-6; 700 mg in patients 7-10; and 840 mg in patient 11. No patient had dose limiting toxicity determined on cycle 1 of DA-TEDDI-R. There were 3 on-study deaths: from progressive disease, infection and ventricular arrhythmia. Ibrutinib PK was completed in patients 1-10 (Table). When corrected for protein binding, CSF penetration was 21.4-100% for ibrutinib and 48-120% for its metabolite. CSF concentrations > IC₅₀were maintained for a median of 4 hours and 8.5 hours at the 560 mg and 700 mg doses, respectively. With ibrutinib alone, 7 of 8 evaluable patients achieved partial responses, and 1 patient had a mixed response. After DA-TEDDI-R, all 5 patients achieved complete remission of which 4 (all R/R) are in remission at 1+, 2+, 3+, and 6+ months, and 1 (previously untreated) patient relapsed at 3 months.

Conclusions: Ibrutinib is active in PCNSL and achieves meaningful CSF concentrations. DA-TEDDI-R is a novel treatment for PCNSL and leverages molecular and therapeutic principles developed for the curative treatment of ABC DLBCL. Accrual continues.