Abstract Background: Primary DLBCL of CNS (PCNSL) that relapses after or is refractory to high-dose methotrexate (HD-MTX) has poor long-term survival of 20%. PCNSL biology includes chronic active BCR signaling targeted by ibrutinib. Ibrutinib with temozolomide, etoposide, liposomal doxorubicin, dexamethasone, and rituximab (TEDDI-R) induces durable remissions in relapsed or refractory PCNSL but carries Aspergillus risk (Lionakis et al. Cancer Cell 2017). We added isavuconazole prophylaxis and report outcomes with escalating ibrutinib doses. Methods: Study conduct has been described (Roschewski et al. ASH 2024). Adults with relapsed or refractory PCNSL were enrolled in a phase 1 study with expansion. Prior BTKi, HIV+, and EBV+ were excluded. Isavuconazole started 3d before ibrutinib and continued throughout therapy. In phase 1, three dose levels of ibrutinib (280/420/560mg) were tested with TEDD-R. Two expansion cohorts received ibrutinib either continuously or on a fixed schedule (d1-10/cycle). Pts received up to 6 cycles without consolidation or maintenance. Tumors were molecularly classified by LymphGen. The primary objective was to determine the highest ibrutinib dose safely given with isavuconazole. Secondary objectives included overall response rate (ORR), PFS, and OS. Results: Thirty pts enrolled, including 10 in phase 1 and 10 each in the expansion cohorts. Median age was 63y (range 40-78), with 6 (20%) ≥70y. All had prior HD-MTX and 5 (17%) had prior stem cell transplant. Nineteen (63%) pts were refractory to HD-MTX. No DLTs were observed; ibrutinib 560mg was used in expansion. Neutropenia occurred in 6% (G3) and 40% (G4) of cycles, with febrile neutropenia in 11%. Thrombocytopenia occurred in 13% (G3) and 14% (G4) of cycles. ≥G3 infections occurred in 53% of pts, most common being UTI (20%), none fungal or opportunistic. Palmar plantar erythrodysesthesia occurred in 17 (57%) pts, managed with liposomal doxorubicin dose reduction. Notable ≥G3 non-hematologic toxicities included venous thromboembolism in 20%, and fatigue, syncope, mucositis, and hypokalemia in 13% pts each. G2 supraventricular arrhythmias occurred in 2 (7%) pts. Twenty-two pts died: 16 (73%) from progression, 2 (9%) from COVID, 1 (5%) from HBV reactivation, and 3 (14%) unknown. ORR was 90% (95% CI, 74-97), including complete response (CR) in 60% (95% CI, 42-75). CRs occurred across LymphGen subtypes: MCD 5 (71%), A53 2 (100%), BN2 1 (100%), and Other 2 (40%). No pt received consolidation. With a median f/u of 5.3y, the 2y PFS was 29% (95% CI, 14-46) and the 2y OS 47% (95% CI, 28-63). Ibrutinib schedule and HD-MTX refractoriness did not affect 2y PFS (P=0.94 and 0.68, respectively). Conclusions: Ibrutinib 560mg is safe across ages in TEDDI-R, and concurrent isavuconazole substantially reduces Aspergillus risk. TEDDI-R achieves high CR rate in relapsed or refractory PCNSL, including HD-MTX refractory disease. Durable remissions occur without consolidation. Cancer Therapy Evaluation Program sponsored this trial [NCT02203526] along with NCI’s Intramural Research Program. Citation Format: Rahul Lakhotia, Christopher Melani, Tatyana Gavrilova, Jagan R. Muppidi, James D. Phelan, Michail S. Lionakis, Kieron Dunleavy, Lode J. Swinnen, Matthias Holdhoff, Catherine Lai, Sami Ibrahimi, Michael Glantz, Jan Drappatz, John A. Butman, Stefania Pittaluga, Kim Johnson, Atekelt Tadese, Hyoyoung Choo-Wosoba, John D. Heiss, William D. Figg, Elaine S. Jaffe, S. Percy Ivy, Richard F . Little, Louis M. Staudt, Mark Roschewski, Wyndham H. Wilson. Final analysis of a Phase 1 study of ibrutinib dose-escalation in TEDDI-R with isavuconazole for relapsed or refractory primary DLBCL of the CNS [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A047.
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