551 Pegasus Skin, a study of SAR444245 (THOR-707, a pegylated recombinant non-alpha IL2) with cemiplimab for the treatment of participants with advanced unresectable or metastatic skin cancers

BackgroundSAR444245 (THOR-707) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. 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. The HAMMER trial, which is the FIH study, shows preliminary encouraging clinical results: initial efficacy and safety profile with SAR444245 monotherapy and in combination with pembrolizumab supporting non-alpha preferential activity, validating preclinical models. The Pegasus Skin Phase 1/2 study will evaluate the clinical benefit of SAR444245 in combination with cemiplimab (anti-PD1) for the treatment of participants with cutaneous squamous cell carcinoma (CSCC) or melanomaMethodsPegasus Skin (NCT04913220) will enroll approximately 80 participants in 2 separate cohorts. In cohort A, participants with a locally advanced, unresectable or metastatic melanoma will receive SAR444245 + cemiplimab as first line (1L) therapy. In cohort B, participants with locally advanced or metastatic CSCC who have not received moe than 2 prior lines of systemic therapy and are not candidates for curative surgery or radiation will receive SAR444245 + cemiplimab. The study will start with a dose escalation to determine the recommended phase 2 dose (RP2D) of SAR444245 when combined with cemiplimab. The starting dose will be 16 μg/kg Q3W (DL1) with a possibility to de-escalate to 8 μg/kg Q3W (DL -1) or escalate to 24 μg/kg Q3W (DL2) based on the occurrence of DLT and overall assessment of safety. Participants enrolled in the Dose Escalation and treated at the RP2D selected for Dose Expansion will be included in the total number of participants for efficacy and safety evaluation. Participants will receive study treatment until disease progression, unacceptable toxicity, or completion of 35 cycles. Cemiplimab will be administered 350 mg per label, Q3WAcknowledgementsThe Pegasus Skin study is sponsored by SanofiTrial RegistrationNCT04913220Ethics ApprovalAll applicable ECs are obtainedConsentAll participant consents are obtaine

Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SAR439459, a TGFβ inhibitor, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors:Findings from a phase 1/1b study

SAR439459 (SAR'459), a “second-generation” human anti-transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty-eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness-of-fit plots and adequately described the observed data by a two-compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment-emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients.</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements