Phase 1 Study of Escalating Doses of Ibrutinib in Teddi-R with Isavuconazole for Relapsed and Refractory Primary DLBCL of the CNS

Background: Primary DLBCL of the CNS (PCNSL) that relapses after or is refractory to frontline high-dose methotrexate (HD-MTX) has a very poor prognosis with a median overall survival of <4 months. The underlying biology of PCNSL includes chronic active BCR signaling targeted by ibrutinib. We have previously shown that ibrutinib with temozolomide, etoposide, liposomal doxorubicin, dexamethasone, and rituximab (TEDDI-R) induces durable remissions in relapsed/refractory PCNSL without the need for consolidation, but risks Aspergillus (Lionakis et al. Cancer Cell 2017). Here, we report clinical outcomes with the antifungal agent isavuconazole added to escalating doses of ibrutinib in the TEDDI-R regimen for relapsed/refractory PCNSL. Methods: Pts with relapsed/refractory PCNSL, age ≥18, ECOG PS ≤2 (unless due to disease), and adequate organ function were enrolled onto a phase 1 study with 2 expansion cohorts. Previous BTKi, HIV+, and EBV+ were excluded. Pts had baseline MRI brain, FDG-PET brain and body, Ommaya placed, CSF with flow cytometry, and eye exam. Isavuconazole 200mg BID started 3 days prior to ibrutinib then 200mg daily throughout therapy. In phase 1, three dose levels of ibrutinib (280mg, 420mg, 560mg) were tested with isavuconazole and TEDD-R. Two expansion cohorts were tested using ibrutinib continuously for 21 days/cycle and as a fixed-dose 10 days/cycle. Pts received up to 6 cycles of TEDDI-R with intra-Ommaya cytarabine and no planned maintenance or consolidation. Brain MRI was performed after cycles 1, 2, 4, and 6 to determine response. All remissions by MRI were confirmed with FDG-PET brain and CSF flow cytometry. Surveillance brain MRI were q3m for 1y, q4m x 1y, q6m x 1y, then annually. Primary objective was to identify the safe dose of ibrutinib. Secondary objectives included overall response rate, PFS, and OS. Results: 30 pts were enrolled, including 10 in the phase 1 portion and 10 each in the continuous and fixed-dose ibrutinib expansion cohorts. Twenty-one (70%) pts were male w/median age 63 (range 40-78), including 6 pts (20%) aged ≥70y. Ethnic distribution included White (60%), Hispanic (20%), Asian (13%), and Black (7%). All 30 pts had prior HD-MTX and 5 (17%) had prior stem cell transplant. Seventeen (57%) pts had primary refractory disease and had not previously achieved remission. No DLTs were observed and ibrutinib 560mg was used in expansion. Neutropenia occurred in 6% (G3) and 40% (G4) of cycles, while febrile neutropenia occurred in 11%. ≥G3 infection occurred in 57% of pts, but none were opportunistic (e.g. Aspergillus). Thrombocytopenia occurred in 13% (G3) and 12% (G4) of cycles. Palmar-plantar-erythrodysesthesia occurred in 17 (57%) pts which led to dose reduction of liposomal doxorubicin. Notable ≥G3 non-hematologic toxicities per patient included generalized weakness (17%), syncope (13%), venous thromboembolism (13%), mucositis (13%), hypokalemia (13%), hypertension (10%), and supraventricular tachycardia/atrial fibrillation (7%). Eighteen deaths occurred: 15 (83%) were due to progression, 2 (11%) due to COVID, and 1 (6%) from hepatitis B reactivation. In 28 patients evaluable for response, the overall response rate was 86% (95% CI: 69%, 94%), including a complete response rate of 68% (95% CI: 49%, 82%). After a median f/u of 42 months, the 2-year PFS was estimated at 28% (95% CI, 15-50) and the 2-year OS was estimated at 47% (95% CI, 31-69). No difference was observed in 2-year PFS or OS between dose schedules of ibrutinib. Conclusions: Ibrutinib 560mg is safely administered to patients of all ages in the TEDDI-R regimen with concomitant isavuconazole which greatly reduces the risk of Aspergillus. TEDDI-R induces a high rate of complete response in patients with relapsed/refractory PCNSL including those refractory to HD-MTX. Remissions can be durable without consolidation. This clinical trial [NCT02203526] was sponsored by the Cancer Therapy Evaluation Program with support from the Intramural Research Program of NCI at NIH.