Isatuximab, an anti‐CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open‐label, single‐arm, multicenter, phase 1/2 trial investigated the ...tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose‐limiting toxicities occurred; the recommended dose for the single‐arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high‐risk cytogenetic abnormalities had comparable results. In phase 2, the median progression‐free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high‐risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.
This open‐label, single‐arm, multicenter phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). The results demonstrated that isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM, including high‐risk cytogenetic patients.
BackgroundSAR445710 is a targeted cytokine comprised of a fusion antibody combining a fully human, high affinity anti-human Programmed Death Ligand 1 (PD-L1) IgG1 antibody with the human IL-15 ...receptor alpha (IL-15Rα) sushi domain and human IL-15. SAR445710 and its mouse cross-reactive surrogate molecule have been extensively characterized by in vitro and in vivo studies and demonstrated robust efficacy and therapeutic benefits compared to IL-15 alone. Specifically, SAR445710, potentially leverages PD-L1 targeting to deliver IL-15 to the tumor microenvironment.MethodsThis was a phase 1, open-label, multiple ascending dose, multi-center study in patients with metastatic or locally advanced solid tumors (NCT04242147). Dose escalation followed a ‘3+3’ design with the occurrence of dose limiting toxicity (DLT) evaluated over the first 28 days. Bi-weekly (Q2W) and weekly (QW) dosing schedules were evaluated at doses ranging from 3–400 μg/kg (Q2W) and 50–300 μg/kg (QW). The primary objective was to assess the safety and tolerability of SAR445710 monotherapy.ResultsAs of July 31, 2023, 39 patients (median age, 61.5 years, and 46.15% females) were treated in dose escalation with 27 patients on Q2W schedule and 12 on QW schedule. There were three DLTs in the Q2W dose escalation, two Grade 3 cytokine release syndrome at 400 μg/kg and one Grade 3 pneumonitis at 200 μg/kg. No DLTs were observed in the QW schedule. The maximum tolerated dose (MTD) in the Q2W schedule was 200 μg/kg. Pyrexia (57.1%) and chills (42.9%) were the most common treatment-related adverse events. These were mostly Grade 1–2 that resolved with supportive management. Best overall response achieved among the Q2W and QW schedules was stable disease. On-target and expected pharmacodynamics for IL-15 agonisms were observed. SAR445710 had a potent effect on peripheral NK and CD8 T cell expansion. Ki67 expression in NK and T cells peaked on day 2 to day 3 post-treatment. There was no clear sign that T cells developed an exhaustion phenotype after repeated SAR445710 dosing. SAR445710 showed a non-linear pharmacokinetic profile from 3–400 µg/kg (Q2W), as expected for targeted antibodies. Enrolment continues in the QW schedule.ConclusionsSAR445710 demonstrated a manageable toxicity profile with on-mechanism pharmacodynamics consistent with IL-15 agonism.AcknowledgementsThis study is funded by Sanofi. Medical writing support was provided by Latika Saxena of Sanofi.Trial RegistrationNCT04242147Ethics ApprovalThis study obtained ethics approval from WIRB.
BackgroundSAR445877 is a fusion protein of high affinity anti-programmed cell death protein 1 (PD1) antibody combined with a detuned interleukin 15 (IL15) (complexed with IL15 receptor sushi domain). ...SAR445877, via its anti-PD1 moiety, binds to PD-1-expressing T and natural killer (NK) cells and potentially allows for a targeted expansion and activation of CD8+ T and NK cells expressing both PD1 and IL2/15Rβγ. Nonclinical studies have demonstrated the potential of SAR445877 as an immune-modulatory agent with good tolerability and therapeutic benefits in various neoplastic disease models including programmed cell death ligand 1 (PD-L1)/PD-L1 resistant models as a monotherapy.1 SAR445877 treatments in preclinical models showed increased cytotoxic immune cell recruitment to tumor microenvironment, prolonged survival, and tumor clearance.2 MethodsThis is a first in human, open-label, multicenter, dose escalation and expansion phase 1/2 study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activities of SAR445877 administered intravenously as a single agent in adult participants with advanced unresectable or metastatic solid tumors (NCT05584670). The study is conducted in 2 parts. The Part 1 (dose escalation) will determine the maximum tolerated dose or maximum administered dose per occurrence of dose limiting toxicities in the first 28-days (cycle 1 and 2), recommended dose(s), and the overall safety and tolerability profile of SAR445877. A multicohort Part 2 (dose expansion) would assess the safety and preliminary efficacy of SAR445877 (2 dose levels in at least 1 indication, as applicable) and will include cohorts with advanced solid tumors regardless of the tumor proportion score/combined positive score and cohort with a negative expression of the PDL1. Approximately, 240 participants will be enrolled, of which nearly 75 participants will be enrolled in the Part 1 and 165 participants in the Part 2. Adverse effects will be assessed per National Cancer Institute, Common Terminology Criteria for Adverse Events version 5.0 and American Society for Transplantation and Cellular Therapy consensus grading. Tumor response will be determined according to Response Evaluation Criteria in Solid Tumors criteria. Dose escalation Part 1 is conducted in US, Spain and Netherlands. The study is enrolling participants.Trial RegistrationNCT05584670ReferencesLu D, Polonskaya Z, Pei-Chang C, A novel human anti-PD1/IL15 bi-functional protein with robust anti-tumor activity and low systemic toxicity. J Immunother Cancer. 2020;8(Suppl 3):A1-A559Polonskaya Z, Pei-Chang C, Martimo S, MOA study of KD050, an anti-PD-1/IL-15 bi-functional antibody selectively targeted PD-1 positive tumor-infiltrating lymphocytes resulted in robust anti-tumor activity and low systemic toxicity. Cancer Res. 2022;82(Suppl 12):5215.
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