Abstract CT094: Phase I dose-escalation study evaluating the safety and tolerability of ginisortamab (UCB6114), a first-in-class anti-gremlin-1 monoclonal antibody (mAb), as monotherapy in advanced solid tumors
Authors: Sarker Debashis , Blagden Sarah , Cook Natalie , Evans Thomas R. , Plummer Ruth , Angelakas Angelos , Bashir Saira , Badri Salma El , Mavroeidis Leonidas , Morton Cienne , Muhith Abdul (Moe) , White Mark , Dixon Rupert , Garric Elodie , Mann Joanne , Matthews Ivan , Banerji Udai 
Published: April 2023

Abstract
Effective treatment for gastrointestinal (GI) cancers is a significant unmet need. Gremlin-1, secreted by cancer-associated fibroblasts, downregulates bone morphogenetic proteins (BMP), members of the transforming growth factor β superfamily, resulting in tumor stemness, hyperproliferation, and invasiveness. Ginisortamab, a fully human IgG4P mAb, neutralizes gremlin-1, thus restoring BMP signaling. Preclinical studies showed that ginisortamab binds to gremlin-1 and has antitumor activity in several mouse models, including GI cancers. Here we report the initial findings from Part A (monotherapy dose escalation) of the first-in-human study. ONC001 (NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study assessing the safety, PK/PD, and antitumor activity of intravenous (IV) ginisortamab as monotherapy or in combination with selected standard of care regimens in patients (pts) with advanced solid tumors. ONC001 includes 3 dose escalation modules (Parts A-C) and a dose adaptation module (Part A1). To be eligible for Part A, pts had to be aged ≥18 years (y) with advanced disease, resistant or refractory to standard therapy, with ECOG PS ≤1. We present the primary (safety, tolerability), secondary (PK/PD), and exploratory (antitumor activity) endpoints, as well as the monotherapy RP2D from Part A. At data cutoff (June 20, 2022), 25 pts received ≥1 dose of ginisortamab (median [range] age: 64 [37-74] y; 68% male; 88% White; 36% had &gt;3 lines of prior therapy). The most common tumor type enrolled was colorectal adenocarcinoma (44%). Ginisortamab was escalated using a modified rolling 6 design through 5 levels (100, 250, 500, 1000, and 2000 mg IV Q2W) in 28-day cycles. No DLTs, Grade ≥3 AEs related to ginisortamab, or serious related AEs were observed; the 2000 mg dose was deemed safe for further development. Temporary treatment interruption and study discontinuation due to AEs unrelated to ginisortamab occurred in 7 (28%) and 2 pts (8%), respectively. Ginisortamab PK aligned with expectations from preclinical models for an IgG4 mAb, allowing favorable dosing intervals. Confirmation of target occupancy was demonstrated by increases in total circulating gremlin-1. Antidrug antibody formation was not observed. The best overall response of stable disease was observed in 7/24 pts (29%); 4 pts had a reduction of the sum of the dimensions of their target lesions relative to baseline. Favorable safety and PK/PD data at the maximum dose of 2000 mg and preliminary antitumor activity were observed with the first-in-class anti-gremlin antibody ginisortamab. These data support further evaluation of the efficacy and safety of ginisortamab monotherapy at 2000 mg Q2W, or in combination with standard of care regimens (FOLFOX, trifluridine/tipiracil) in advanced solid tumors.
Citation Format: Debashis Sarker, Sarah Blagden, Natalie Cook, Thomas R. Evans, Ruth Plummer, Angelos Angelakas, Saira Bashir, Salma El Badri, Leonidas Mavroeidis, Cienne Morton, Abdul (Moe) Muhith, Mark White, Rupert Dixon, Elodie Garric, Joanne Mann, Ivan Matthews, Udai Banerji. Phase I dose-escalation study evaluating the safety and tolerability of ginisortamab (UCB6114), a first-in-class anti-gremlin-1 monoclonal antibody (mAb), as monotherapy in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT094.