760 Interim PK/PD, safety and efficacy data of monotherapy dose escalation of a phase 1/2 study with MDNA11 in patients with advanced solid tumors
Notice bibliographique
Résumé
<h3>Background</h3> MDNA11 is an albumin-fused long-acting IL-2 agonist with enhanced affinity for IL-2Rb and no binding to IL-2Ra, resulting in potent CD8<sup>+</sup> T and NK cell activation, limited Treg increase and reduced toxicities.<sup>1</sup> ABILITY (A Beta-only IL-2 ImmunoTherapY) is a Phase 1/2 study evaluating the safety, pharmacokinetic (PK), pharmacodynamic (PD) and preliminary clinical activity of MDNA11 as monotherapy and in combination with Prembrolizumab in pre-treated patients with advanced solid tumors. <h3>Methods</h3> The dose-escalation phase of ABILITY uses a modified 3+3 design to determine the recommended dose for expansion (RDE). Patients received a fixed dose of 3, 10 or 30 μg/kg (dose levels 1–3; DL1–3) by intravenous infusion on a Q2W schedule. Step-up dosing was implemented starting at DL4 where patients received 2 or 3 priming doses prior to the target dose of 60 μg/kg (DL4), 90 μg/kg (DL5) or 120 μg/kg (DL6). Primary endpoints include incidence and severity of adverse events (AEs). Secondary endpoints include assessment of PK, PD and tumor response per RECISTv1.1 and iRECIST <h3>Results</h3> As of June 22, 2023, twenty dose limiting toxicity (DLT)-evaluable patients have been dosed with MDNA11 during monotherapy dose escalation (3–120 μg/kg). Tumor types enrolled included melanoma (n=11), renal cell carcinoma (n=2), pancreatic ductal adenocarcinoma (PDAC; n=2), sarcoma (n=2), tonsillar squamous cell carcinoma (n=1), gastro-esophageal adenocarcinoma (n=1) and lung adenocarcinoma (n=1). PK analysis showed dose-dependent increase in MDNA11 exposure. Immune profiling showed robust lymphocyte expansion, including increase in CD8<sup>+</sup> T and NK cells and limited change in Tregs. There were no DLTs observed. The most common AEs were infusion related reaction (65%) comprising pyrexia (50%), nausea (45%), chills (35%), fatigue (30%) and diarrhea (25%), with the majority being grade 1–2 and resolved within 48–72 hours. Transient (~ 1week duration) transaminases increase was seen in 25% of patients. Tumor response was evaluated in 19 patients. Single-agent activity included stable disease (SD) observed in 6 patients, including a melanoma patient with SD beyond 1.5 year, and an ongoing partial response (PR) in a PDAC patient who had previously progressed on immune checkpoint inhibitor and is currently continuing on MDNA11 for > 1 year. <h3>Conclusions</h3> MDNA11 is well tolerated with no DLTs up to target dose of 120 μg/kg on a Q2W schedule. Evidence of clinical activity includes SD in 6 of 19 patients in addition to a durable PR in a PDAC patient. Data analysis is ongoing to inform RDE selection. <h3>Acknowledgements</h3> We are grateful to all patients participating in this study. <h3>Trial Registration</h3> NCT: 05086692 <h3>Reference</h3> Merchant R, Galligan C, Munegowda MA, <i>et al</i>. Fine-tuned long-acting interleukin-2 superkine potentiates durable immune responses in mice and non-human primate. 2022;<b>10</b>:e003155. <h3>Ethics Approval</h3> The study was conducted with approval from institutional ethics committee and informed consent from participants.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».