Phase I Study of Dose-Adjusted-Teddi-R with Ibrutinib in Untreated and Relapsed/Refractory Primary CNS Lymphoma
Authors: Dunleavy Kieron , Lai Catherine E. , Roschewski Mark , Brudno Jennifer N , Widemann Brigitte , Pittaluga Stefania , Jaffe Elaine S , Lucas Andrea N , Stetler-Stevenson Maryalice , Yuan Constance M. , Harris Pamela , Cole Diane , Butman John A , Little Richard F , Staudt Louis M , Wilson Wyndham H 
Published: October 2019

Abstract
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 (AUCCSF: AUCPLASMA) 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.
Table. Plasma Ibrutinib PK CSF Ibrutinib PK CSF penetration Hours above IC50(0.5nM) Dose 560 mg Cmax(nM) Tmax(h) AUC0-10 (nM•h) T½(h) Cmax(nM) Tmax(h) AUC0-last (nM•h) AUCCSF : AUCPlasma (%) AUCCSF :AUCPlasmaCorrected (%) Plasma CSF 1 502 1 1232 10.2 1.99 2 7.7 (10h) 0.6 23.7 24 4 2 145 2 471 4.6 0.69 2 2.4 (6h) 0.5 21.4 24 2 3 77 2 347 3.1 1.28 2 4.4(6hr) 1.3 55.8 24 4 4 72 1 202 2.6 1.54 4 5.5 (10hr) 2.7 100 24 8 5 162 2 624 8.5 2.0 2 9.2 (10hr) 1.5 54.9 24 10 6 99 1 404 6.3 0.71 2 3.4 (4hr) 1.2 45 24 4 Median 122 1.5 437 5.5 1.4 2 5 1.3 50 24 4 Range 75-502 1-2 202-1232 2.6-10.2 0.7-2 2-4 2.4 9.2 21.4-100 24 2-10 Dose 700mg 7 581 1 2340 5.3 11.1 2 48.6 (24) 1.7 (10) 63 (10) 24 10 8 411 2 1565 2.4 1.63 2 11.9 (10) 0.8 28.1 10 10 9 164 2 865 3.8 0.69 4 3.9(10) 0.45 16.7 24 3 10 577 2 1648 5.4 2.36 2 11.0(10) 0.67 24.8 24 7 Median 494 2 1606 4.6 1.98 2 11.5(10) 0.74 26.5 24 8.5 Range 164-581 1-2 865-2340 2.4-5.4 0.69-11.1 2-4 3.9-48.6 0.45-1.7 16.7-63 10-24 3-10

Disclosures
Staudt: Pharmacyclics LLC, an AbbVie Company: Patents & Royalties, Research Funding; NIH: Patents & Royalties.