Trials in progress - A phase I study of loncastuximab tesirine and rituximab following stereotactic radiosurgery in patients with primary and secondary central nervous system lymphomas (SOLAR)

Abstract

Abstract Background: Central nervous system lymphomas (CNSL) carry a poor prognosis and remain difficult to treat due to limited effective therapies that can cross the blood brain barrier (BBB). While CNSL is rare, the incidence is rising, particularly among patients older than 60 years at diagnosis (median age of 67 years). Although high-dose methotrexate (HDMTX) remains the most effective curative-intent therapy, many older patients have comorbidities precluding its use. Relapsed or HDMTX-ineligible patients have especially poor prognosis, underscoring the urgent need to identify effective, well-tolerated therapeutic alternatives. Stereotactic radiosurgery (SRS) provides targeted radiation at disease sites while sparing the rest of the brain and showed good local control with minimal toxicity when used for patients with CNSL. However, responses are not durable in patients who are HDMTX-ineligible or those who have progressed following HDMTX. Loncastuximab tesirine (lonca) is an anti-CD19 antibody-drug conjugate (ADC) approved for relapsed/refractory diffuse large B-cell lymphoma based on results from the LOTIS-2 trial. Quantitative system pharmacology modeling suggested that lonca administration following radiation-induced BBB disruption by SRS can augment and sustain central drug exposure. Rituximab (R), a standard of care treatment for B-cell non-Hodgkin lymphomas, has demonstrated improved outcomes in patients with primary CNSL due to its ability to cross the BBB. Thus, SRS-induced BBB disruption will facilitate the delivery of lonca-R to tumors in CNS and optimize CNS drug exposure and clinical efficacy. Here, we investigate the safety and feasibility of lonca-R following SRS in patients with primary and secondary CNSL. Study Design and Methods: SOLAR (NCT06607549) is a multicenter, single-arm, open-label, nonrandomized phase 1 study. Eligible patients are ≥18 years with histologically confirmed CNSL who either have relapsed after initial HDMTX or are HDMTX -ineligible and must be a candidate for SRS (with ≤10 CNS lesions each <6 cm). Patients must have adequate end-organ function. Patients with vitreous or retinal involvement alone, leptomeningeal disease, or spinal cord disease are not eligible. Patients receive a fractionated SRS (x 5 days), followed by brain MRI at 4 weeks (+/- 7 days) and subsequent lonca-R initiated within 14 days post-MRI. The study includes a dose escalation phase (phase 1a) and a dose expansion phase (phase 1b). Phase 1a utilizes the Bayesian optimal interval (BOIN) dose escalation design to determine the maximum tolerated dose (MTD) and/or recommended dose (RP2D) for expansion. Dose level 1 (DL1) starts with lonca 0.15 mg/m2 and rituximab 375 mg/m2 (day 1 of each 21-day cycle). A cohort of 3 patients is used for each dose level (two dose levels, DL1 and DL-1) and the MTD is determined based on safety evaluation results. Phase1a (dose selection) will recruit a maximum of 12 patients (6 per dose level). Once the MTD and/or RP2D is established, phase 1b (dose expansion) will enroll an additional 9 patients. As of July 14, 2025, 2 patients have been enrolled. The primary endpoint is MTD and/or RP2D, and secondary endpoints include overall response rate and complete response rate. Exploratory endpoints include duration of response, progression-free survival, and overall survival. Correlative analysis includes minimal residual disease testing on banked diagnostic tissue and CSF from different timepoints.