pegenzileukin (SAR444245)

P2, N=14, Active, not recruiting, Sanofi | Trial completion date: Sep 2024 --> Jan 2025

P1/2, N=46, Active, not recruiting, Sanofi | N=80 --> 46

P2, N=138, Active, not recruiting, Sanofi | N=280 --> 138 | Trial completion date: Mar 2024 --> Sep 2024

P2, N=59, Active, not recruiting, Sanofi | N=120 --> 59 | Trial completion date: Aug 2024 --> Feb 2025

P2, N=14, Active, not recruiting, Sanofi | N=50 --> 14

P2, N=107, Active, not recruiting, Sanofi | N=160 --> 107 | Trial completion date: Feb 2024 --> Jan 2025

P1/2, N=197, Recruiting, Sanofi | N=123 --> 197 | Trial completion date: Nov 2028 --> Dec 2027 | Trial primary completion date: Nov 2028 --> Dec 2027

P2, N=280, Active, not recruiting, Sanofi | Trial completion date: Sep 2023 --> Mar 2024

P2, N=280, Active, not recruiting, Sanofi | Trial completion date: Jan 2024 --> Sep 2023

SAR444245 treatment of exhausted antigen-specific or CAR T cells restored functionality and alleviated T cell dysfunction in vitro and in vivo . These data suggest that SAR444245 rescue of CAR T cell exhaustion through maintenance of CAR T cell proliferative capacity, cytotoxicity, and polyfunctionality and provide rationale for future clinical study of SAR444245 with CAR T cells. Diffuse large B cell lymphoma, CAR-T, Cancer immunotherapy, Interleukin-2

P1/2, N=300, Recruiting, Synthorx, Inc, a Sanofi company | Trial completion date: Mar 2024 --> Apr 2026 | Trial primary completion date: Mar 2024 --> Apr 2026

Materials and SAR'245 was given IV as monotherapy Q2W [Cohort A], monotherapy Q3W [Cohort B] or Q3W + IV pembrolizumab 200 mg Q3W/400 mg Q6W [Cohort C] and Q3W + Cetuximab [Cohort D]. In early oncology studies, joint modeling using non-invasive biomarkers, including MoA and response biomarkers, and a safety profile can inform dose-response relationships and support RP2D selection. This innovative integrative modeling will guide clinical study design. Studies of SAR'245 that further explore the dosing and scheduling are on-going.

We show that SAR444245 (non-alpha IL2) can activate huNK cells in vivo in all developed huIL-15 transgenic models and confirmed the minimal effective dose by flow-cytometry PD studies. We show the efficacy of both reference and internal ADCC-enhanced antibodies in disseminated tumor models in our humanized huIL-15 transgenic mice. In addition, we performed a deep characterization of huNK cells in huIL-15 transgenic models, using a 28-color flow cytometry panel centered on NK cell biology and profiled them transcriptionally by single cell RNA Seq in a disseminated B-cell lymphoma model.Overall, we have developed robust models sustaining fully functional huNK cells that can be proficiently recruited in vivo by various NK-based therapeutics and can be used to evaluate the efficacy of combination therapies.

In early oncology studies, joint modeling using non-invasive biomarkers, including MoA and response biomarkers, and a safety profile can inform dose-response relationships and support RP2D selection. This innovative integrative modeling will guide clinical study design. Studies of SAR’245 that further explore the dosing and scheduling are on-going.

P2, N=50, Active, not recruiting, Sanofi | Trial completion date: Sep 2023 --> Sep 2024

P2, N=280, Active, not recruiting, Sanofi | Trial primary completion date: Jan 2024 --> Jul 2023

P2, N=50, Active, not recruiting, Sanofi | Trial completion date: May 2025 --> Sep 2023 | Trial primary completion date: Apr 2025 --> Aug 2023

P1/2, N=300, Recruiting, Synthorx, Inc, a Sanofi company | Trial completion date: Aug 2023 --> Mar 2024 | Trial primary completion date: Aug 2023 --> Mar 2024

In animal models, SAR444245 showed anti-tumor benefits, and with no severe side effects, both as a single agent as well as when combined with anti-PD1 compared with historical data from aldesleukin. Both primary endpoints are based on Lugano response criteria 2014. The main secondary endpoints include safety and other efficacy assessments.

P2, N=280, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting

P2, N=50, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting

P1/2, N=300, Recruiting, Synthorx, Inc, a Sanofi company | Trial completion date: Apr 2023 --> Aug 2023 | Trial primary completion date: Apr 2023 --> Aug 2023

P2, N=50, Recruiting, Sanofi | Trial completion date: Sep 2025 --> Apr 2025 | Trial primary completion date: Aug 2025 --> Mar 2025

P2, N=280, Recruiting, Sanofi | Trial completion date: Jul 2023 --> Jan 2024 | Trial primary completion date: Jul 2023 --> Jan 2024

P1/2, N=300, Recruiting, Synthorx, Inc, a Sanofi company | Trial completion date: Dec 2022 --> Apr 2023 | Trial primary completion date: Dec 2022 --> Apr 2023

P2, N=50, Recruiting, Sanofi | N=25 --> 50

P1/2, N=300, Recruiting, Synthorx, Inc, a Sanofi company | Trial completion date: Apr 2022 --> Dec 2022 | Trial primary completion date: Apr 2022 --> Dec 2022

P2, N=60, Ongoing, Sanofi-Aventis Recherche & Développement

P2, N=350, Ongoing, Sanofi-Aventis Recherche & Developpement

P2, N=280, Recruiting, Sanofi | Not yet recruiting --> Recruiting

P1/2, N=300, Recruiting, Synthorx, Inc, a Sanofi company | N=200 --> 300

P2, N=280, Not yet recruiting, Sanofi

initial efficacy and safety profile with SAR444245 monotherapy and in combination with pembrolizumab or with cetuximab support a non-alpha preferential activity, validating preclinical models. The Pegasus Head and Neck Ph 2 study will evaluate the clinical benefit of SAR444245 in combination with other anticancer therapies for the treatment of patients with R/M HNSCC. Methods The Pegasus Head and Neck will enroll approximately 272 patients in 4 separate cohorts concurrently.

In animal models, SAR444245 showed anti-tumor benefits, but with no severe side effects, both as single agent and when combined with anti-PD1 comparing with historical data from aldesleukin...In cohort A3, patients with 1L non-squamous NSCLC will receive SAR444245 + pembrolizumab + pemetrexed + carboplatin/cisplatin. In cohort B1 & B2 patients with 2/3L NSCLC who have progressed on a checkpoint inhibitor (CPI)-based therapy will receive SAR444245 + pembrolizumab, or SAR444245 + pembrolizumab + nab-paclitaxel... initial efficacy and safety profile with SAR444245 monotherapy and in combination with pembrolizumab support a non-alpha preferential activity, validating preclinical models. The Pegasus Lung Ph2 study will evaluate the clinical benefit of SAR444245 in combination with other anticancer therapies for the treatment of patients with lung cancer or pleural mesothelioma Methods The Pegasus Lung (NCT04914897) will enroll approximately 354 patients in 6 separate cohorts concurrently or sequentially. In cohorts A1 & A2, patients with first line (L) NSCLC will receive SAR444245 + pembrolizumab.

Combination with pembrolizumab and cetuximab leveraged SAR44245’s effects on CD8 T and NK cells. Trial Registration NCT04009681

In animal models, THOR-707 improved the anti-tumor benefits of aldesleukin, but without its severe side effects, both as single agent and combined with anti-PD1. Dose escalation continues. NCT04009681

Part 2 patients (pts) received escalating doses of THOR-707 with pembrolizumab 200 mg IV (Cohort C) following a 3+3 DED to identify the MTD and/or RP2D of the combination. Conclusions THOR-707 demonstrated encouraging biomarker data analogous to the not-α IL-2 effect observed in preclinical models with no indicators of VLS in this ongoing trial. Clinical trial information: NCT04009681