Phase I Results of Acalabrutinib in Combination with Durvalumab in Primary Central Nervous System Lymphoma: Safety, Efficacy, and Central Nervous System Penetration

Background: Primary central nervous system lymphoma (PCNSL) is a rare, but aggressive subtype of non-Hodgkin lymphoma restricted to the brain, spinal cord, or eyes. Outcomes in relapsed/refractory (R/R) disease are poor with a median survival of 6 mo. Both Bruton tyrosine kinase inhibitors (BTKis) and immune checkpoint inhibitors (ICIs) have demonstrated activity in CNS lymphomas. We hypothesized that the combination of acalabrutinib and durvalumab would be well tolerated and demonstrate activity in patients (pts) with PCNSL. Here we present the results of the phase I portion of the combination of acalabrutinib and durvalumab in R/R CNS lymphoma, as well as data regarding CNS penetration. Methods: Pts were enrolled at Washington University in St. Louis and the Ohio State University. Adults with confirmed CNS lymphoma without concurrent systemic disease were eligible after >1 prior CNS-directed therapy. Pts with prior exposure to BTKis and ICIs were excluded. The primary objective was to determine safety and tolerability of acalabrutinib and durvalumab and establish the recommended phase II dose (RP2D). The secondary objective was to evaluate the preliminary efficacy of the combination. Exploratory endpoint was to evaluate pharmacokinetics of acalabrutinib (ACP-196) and its active metabolite (ACP-5862) in plasma and cerebrospinal fluid (CSF), with samples collected at one timepoint between cycle 1 day 8 and cycle 2 day 1. Acalabrutinib was administered at 100 mg twice daily (DL1) or 200 mg twice daily (DL2) continuously along with durvalumab 1500 mg IV on day 1 of a 28-day cycle. The phase I study was conducted in a 3+3 design. Dose-limiting toxicities (DLTs) were assessed during the first 12 weeks of treatment and the dose level was deemed tolerable if <2/6 DLTs were observed. DLTs were defined as: ≥grade 3 non-hematologic toxicities; ≥grade 4 hematologic toxicities; neutropenic fever; thrombocytopenia with clinically significant bleeding; ≥grade 2 pneumonitis, neuropathy, myositis; any bullous rash; or toxicities leading to treatment delay of >21 days. Results: The phase I portion of the trial accrued 13 pts from 9/2021 to 11/2023 with a median age of 74 (range 38-83). All pts were white and 8/13 female. 23.1% were GCB subtype, 61.5% non-GCB subtype, and 15.4% unknown. Median number of prior therapies was 2 (range 1-3). The first 3 pts enrolled had secondary CNS lymphoma and experienced progression with 2 DLTs (grade 4 neutropenia, grade 3 pneumonia). The study was then amended to restrict enrollment to PCNSL. At DL1, 6 pts with PCNSL were enrolled and experienced no DLTs. One additional pt at DL1 was replaced due to worsening disease in cycle 1. At DL2, 3 pts were enrolled and 2 experienced DLTs (grade 3 transaminitis, grade 3 diarrhea). Therefore, acalabrutinib 100mg BID with durvalumab 1500mg IV was deemed RP2D. Treatment-related adverse events (AEs) of any grade occurred in 13 (100%) pts. Grade ≥3 AEs occurred in 9 (69%) pts. Grade 3 AEs included lymphopenia (3), pneumonia (3), leukopenia (2), anemia (1), diarrhea (1), hypertension (1), transaminitis (1), and acute kidney injury (1). Only grade 4 AE was sepsis with neutropenia (1). Immune-mediated toxicities included rash (n=3, all grade 2), diarrhea (n=3; grade 1: 2; grade 3: 1), transaminitis (n=2; grade 2: 1, grade 3: 1). Of 10 PCNSL pts, ORR was 40% (CR/CRu 40%). 1/3 had a CR (33%) at DL2 and 3/7 (42.8%) at DL1. 4 pts died due to disease progression and 3 remain in CR (at 72, 44 and 27 weeks, respectively). One pt who achieved CR had progression at 7 weeks. One pt in CR proceeded to consolidative autologous stem cell transplantation. Of 9 pts who had plasma available for analysis, all had detectable plasma concentrations of ACP-196 and ACP-5862. Of 8 pts who had CSF available for analysis, 5 (62.5%) had detectable ACP-196 concentrations (median 4.60 ng/dL, range 2.75-10.6 ng/dL) and only 2 (25%) had detectable ACP-5862 concentrations (median 7.06 ng/dL); both were treated at DL2. Conclusion: Durvalumab 1500mg IV (day 1) and acalabrutinib 100 mg twice daily (days 1-28) of a 28-day cycle demonstrates clinical activity in pts with R/R PCNSL with manageable side effect profile. Responses were not seen in SCNSL (n=3). This is the first study to demonstrate that acalabrutinib (ACP-196) has CSF penetration at acalabrutinib 100-200mg BID. The study is ongoing to further understand efficacy of the combination and is currently enrolling to the dose expansion (NCT 04462328).