Singer, Samuel

Background: The rising incidence of PCNSL in the elderly represents an unmet need with an undefined standard approach [Villano Br J Cancer 2011]. High-dose methotrexate-based (HD-MTX) therapy is feasible and effective in older patients, but outcomes in this population remain poor. Despite high response rates to HD-MTX induction therapy, poor candidacy for intensive consolidative therapy results in transient disease control that may benefit from maintenance strategies [David Am J Hematol 2023]. Lenalidomide (len) has demonstrated activity in PCNSL even at low doses and represents a potential alternative to consolidation considering its extensive use in maintenance settings [Vu Br J Haematol 2019]. Anecdotal activity in PCNSL by checkpoint inhibitors such as nivolumab (nivo) has been reported [Nayak Blood 2017], and its immune response may be enhanced by len [Görgün Clin Cancer Res 2015]. A051901 evaluates the feasibility of the addition of len and nivo to rituximab (R) and HD-MTX as first line induction therapy followed by len-nivo maintenance in elderly patients with PCNSL not eligible for intensive consolidation. Study Design and Methods: This is a single-arm phase 1 multicenter US study (NCT04609046) conducted by the Alliance for Clinical Trials in Oncology with a traditional 3+3 design. Eligible patients are 18 years of age or older with untreated diffuse large B-cell lymphoma PCNSL diagnosed through brain biopsy or resection, or cerebrospinal (CSF) or vitreous fluid not considered candidates for high dose chemotherapy consolidation. This study is available to all eligible patients, regardless of race, gender, or ethnic origin. Patients must have adequate end-organ function including creatinine clearance of at least 50 mL/min. Use of systemic corticosteroids for disease control to be tapered after initiation of therapy is allowed. Induction consists of six 14-day cycles with rituximab 500 mg/m2 i.v. on day 1, HD-MTX 3g/m2 i.v. on day 2. In the most recent treatment schedule, a 5-day course of lenalidomide PO at different dose levels (dose level (DL) 1 = 10 mg, DL2 = 15 mg, DL3 = 20 mg) is initiated immediately after adequate clearance of HD-MTX. Once a maximum tolerated dose (MTD) of len is defined, a subsequent cohort will evaluate the addition of nivo 240 mg i.v. to the day 14 of the induction cycle of R-HD-MTX plus len at the MTD. Patients who present any clinical benefit from induction with at least stable disease by International PCNSL Collaborative Group response criteria are eligible for maintenance - twelve 28-day cycles of therapy with len 15 mg PO from day 1 to day 21 (regardless of dose during induction) +/- nivo 480 mg i.v. on day 1 (for those who received len and nivo during induction). The primary endpoint of the induction therapy is the MTD of len when given in combination with R-HD-MTX; the primary endpoint of maintenance is its feasibility, defined as the proportion of patients able to remain on maintenance for at least 6 cycles. As of July 2024, 16 patients have been enrolled with a maximum expected sample size of 47 patients with the assumption of 75% of patients being eligible to proceed with maintenance and 50% of those who begin maintenance not progressing in the first 6 cycles. Overall response, adverse events, progression-free and overall survival will be evaluated in all eligible patients with a focus on the outcome of patients treated at the MTD. For patients who consent to biobanking, diagnostic tissue, peripheral blood and CSF from different timepoints are collected and banked with planned exploratory analyses including whole exome sequencing, circulating tumor DNA, proteomics, metabolomics. Support: U10CA180821, U10CA180882. https://acknowledgments.alliancefound.org.

Abstract Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.