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 (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. | | 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 : AUCPlasma Corrected (%) | 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 | Table. Disclosures Staudt: Pharmacyclics LLC, an AbbVie Company: Patents & Royalties, Research Funding; NIH: Patents & Royalties.