Abstract CT147: Phase 1 dose escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients with advanced solid tumors
Notice bibliographique
Résumé
Abstract Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine, which is highly expressed in a subset of tumors and correlates with poor prognosis. LIF is hypothesized to contribute to tumor microenvironment immunosuppression and regulation of cancer stem cells. MSC-1 is a first-in-class humanized IgG1 monoclonal antibody that potently and selectively inhibits LIF. In pre-clinical models, MSC-1 decreases tumor growth through inhibition of STAT3 signaling, promoting immune stimulatory macrophages and increasing tumor infiltration of CD8 T and NK cells. The Phase Ia clinical study employed an accelerated 3 + 3 escalation design to explore safety and tolerability, dose-limiting toxicities (DLTs), preliminary efficacy, define a recommended phase II dose (RP2D), and evaluate exploratory tumor biomarkers. Eligible patients had advanced relapsed/refractory solid tumors and received treatment with MSC-1 intravenously (75mg-1500 mg) once every 3-weeks as a single agent until disease progression. The three highest dose cohorts were expanded to further assess safety, PK, engagement of LIF in the periphery, and assess immuno-regulatory tumor activity in matched pre- and on-treatment tumor biopsies. Forty-one patients (pts) were enrolled (14 in dose escalation; 27 in expanded cohorts) with the last pt completing the study on September 23, 2019. The most common tumor types were pancreatic (13), colorectal (5), head & neck (4) and ovarian (4). Pts had received a median of 3 prior lines of therapy. All pts experienced at least one adverse event (AE). The most common considered drug-related AEs were fatigue (N=8, 20%) and gastrointestinal disorder (N=8, 20%), and there was 1 considered drug-related SAE (Gr 2 osteonecrosis of jaw in a head and neck cancer patient who previously received radiation to the area and denosumab). There were no Dose Limiting Toxicities observed during the first cycle of treatment and 2 pts discontinued treatment due to AEs. The PK profile of MSC-1 was linear with an estimated terminal half-life of ∼13 days and benign anti-drug antibody profile. There was evidence of durable peripheral saturation of LIF binding demonstrating high level of target engagement. Results supported the selection of a RP2D of 1500 mg Q3W. Prolonged stable disease (≥ 16 weeks) was observed in 9 pts. Analysis of paired biopsies collected from matched metastatic lesions supported MSC-1 mediated STAT3 signaling inhibition, stimulatory (M1) to suppressive (M2) macrophage skewing in the majority of paired biopsies evaluated and increased CD8 T-cell infiltration in a subset of samples. Single agent MSC-1 was well tolerated in doses ranged from 75 mg to 1500 mg IV OD in patients with advanced solid tumors, showed promising activity as an anti-cancer therapy, and is Phase 1b/2 ready for combination with other agents. The updated final safety, efficacy, PK, LIF stabilization analyses, and tumor biopsy data will be presented. Citation Format: Alison Schram, Erkut Borazanci, Irene Brana, Maria Vieito Villar, Elena Garralda, Anna Spreafico, Marc Oliva, Nehal Lakhani, Robert Wasserman, Kimberly Hoffmann, Robin Hallett, Judit Anido, Dorotea Maetzel, Patricia Giblin, Enda Moran, Adrianne Kelly, Joan Seoane, Daniel D. Von Hoff, Lillian Siu, Josep Tabernero. Phase 1 dose escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT147.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».