selicrelumab (RG7876)

Two independent studies in cynomolgus macaque (Macaca fascicularis) studies were performed to further evaluate, potentially immunotoxicological effects associated with drug-induced adverse events seen in human subjects. Studies conducted in monkeys showed that when selicrelumab is administered at doses currently used in clinical trial patients, via subcutaneous injection, it is safe and effective at stimulating a systemic immune response.

In this review, we present the current understanding of the mechanism of action for CD40, along with results from the clinical development of agonistic human CD40 antibodies in cancer treatment (selicrelumab, CDX-1140, APX005M, mitazalimab, 2141-V11, SEA-CD40, LVGN7409, and bispecific antibodies). This review also examines the safety profile of CD40 agonists in both preclinical and clinical settings, highlighting optimized dosage levels, potential adverse effects, and strategies to mitigate them.

P1/2, N=340, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P1/2; Active, not recruiting --> Recruiting

P1/2, N=340, Recruiting, Hoffmann-La Roche | Trial completion date: Jun 2024 --> Oct 2026 | Trial primary completion date: Jun 2024 --> Oct 2025

P1/2; N=133 --> 242 | Trial completion date: May 2024 --> May 2026 | Trial primary completion date: May 2024 --> May 2026

P1/2; N=280 --> 133

P1/2; Recruiting --> Active, not recruiting | Trial completion date: Sep 2023 --> May 2024 | Trial primary completion date: Sep 2023 --> May 2024

P1/2; Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Mar 2023 --> Sep 2023

P1/2, N=290, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P1/2, N=290, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Nov 2022 --> Jun 2024 | Trial primary completion date: Nov 2022 --> Jun 2024

P1/2, N=290, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

Taken together, these novel insights into selicrelumab-stimulatory effects in CLL may be considered for developing new therapeutic strategies, particularly in combination with obinutuzumab.

This unparalleled examination of CD40 therapeutic mechanisms in patients provides insights for design of subsequent clinical trials targeting this pathway.

P1/2, N=290, Recruiting, Hoffmann-La Roche | Trial completion date: Nov 2021 --> Nov 2022 | Trial primary completion date: Nov 2021 --> Nov 2022

The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.

Here, we performed a neoadjuvant clinical trial of agonistic CD40 mAb (selicrelumab) administered intravenously with or without chemotherapy (gemcitabine and nab-paclitaxel) to 16 resectable patients with pancreatic ductal adenocarcinoma (PDAC) prior to surgery followed by adjuvant chemotherapy and CD40 mAb. This study provides proof-of-concept in patients that agonistic CD40 mAb alters the TME, enhances T-cell infiltration, and modulates systemic inflammatory responses. These findings inform design of next-generation CD40 clinical trials.

Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses.

Control treatments were gem+nabP in PDAC, capecitabine in TNBC, and regorafenib in CRC. Preliminary efficacy was observed for atezo+seli+gem+nabP in PDAC. Together with preliminary evidence of on-treatment pharmacodynamic effects in CRC and TNBC tumor samples, CD40 agonist strategies warrant further investigation.

Control treatments were gem+nabP in PDAC, capecitabine in TNBC, and regorafenib in CRC. Preliminary efficacy was observed for atezo+seli+gem+nabP in PDAC. Together with preliminary evidence of on-treatment pharmacodynamic effects in CRC and TNBC tumor samples, CD40 agonist strategies warrant further investigation.

P1/2, N=280, Recruiting, Hoffmann-La Roche | Trial completion date: May 2023 --> Jan 2023 | Trial primary completion date: May 2023 --> Jan 2023

P1/2; Trial completion date: Feb 2022 --> Nov 2021 | Trial primary completion date: Feb 2022 --> Nov 2021

P1, N=140, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P1/2; Trial completion date: Sep 2020 --> Feb 2022 | Trial primary completion date: Nov 2019 --> Feb 2022

P1, N=142, Active, not recruiting, Hoffmann-La Roche | N=230 --> 142

P1, N=230, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | Trial completion date: Jun 2019 --> Oct 2019 | Trial primary completion date: Jun 2019 --> Oct 2019

P1, N=230, Recruiting, Hoffmann-La Roche | Trial completion date: Oct 2019 --> Jun 2019 | Trial primary completion date: Oct 2019 --> Jun 2019

P1, N=38, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed | N=146 --> 38 | Trial completion date: Jul 2018 --> Apr 2018 | Trial primary completion date: Jul 2018 --> Apr 2018

Trial Registrationl This study is registered on Clinicaltrials.gov: NCT02665416 ; Background Selicrelumab is a fully human agonistic IgG2 monoclonal antibody to CD40, a member of the TNFreceptor superfamily expressed on antigenpresenting cells (APC), endothelial cells and some tumors. The combination demonstrated a favorable safety profile with no evidence for systemic autoimmune toxicity. The results triggered an expansion of the study in selected tumor indications with 16mg SC selicrelumab in combination with bevacizumab (anti- VEGF).

P1/2; Trial completion date: Apr 2020 --> Sep 2020

P1; N=170; Recruiting; Sponsor: Hoffmann-La Roche; Trial completion date: Nov 2019 --> Jun 2020; Trial primary completion date: Nov 2019 --> Jun 2020

P1/2; N=120; Not yet recruiting; Sponsor: Hoffmann-La Roche

P1; N=38; Completed; Sponsor: Hoffmann-La Roche; Active, not recruiting --> Completed; N=146 --> 38; Trial completion date: Jul 2018 --> Apr 2018; Trial primary completion date: Jul 2018 --> Apr 2018

P1, N=146, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting