Abstract CT097: A first-in-human phase I dose escalation study of the OX40 agonist MOXR0916 in patients with refractory solid tumors
Notice bibliographique
Résumé
Abstract Background: OX40 is a co-stimulatory receptor that is transiently expressed by T cells upon antigen recognition. In murine models, OX40 engagement by an agonist anti-OX40 antibody can promote durable tumor regression associated with co-stimulation of effector T cells and reduction of regulatory T cells. MOXR0916 is a humanized effector-competent agonist IgG1 monoclonal antibody that targets OX40. Methods: A Phase I, open-label, multicenter study was conducted to evaluate the safety and pharmacokinetics (PK) of MOXR0916 in patients (pts) with locally advanced or metastatic refractory solid tumors that have progressed after available standard therapy. MOXR0916 was administered at fixed doses every 3 weeks (q3w), and treatment beyond RECIST progression was permitted in the absence of clinical deterioration. A 3+3 dose-escalation was conducted in immunotherapy-naïve pts with a 21-day window to evaluate dose-limiting toxicity (DLT). A dedicated expansion cohort enrolled pts who consented to serial tumor biopsies, enabling immune profiling by immunohistochemistry and gene expression methods. In the biopsy cohort, prior immunotherapy with adequate washout was permitted, provided there was no history of Grade (G) ?3 immune-mediated adverse events (AEs). Results: Enrollment in the dose-finding phase of the trial is complete, with 34 pts treated across 10 dose escalation cohorts (dose levels 0.2-1200 mg) and 36 pts treated in the serial biopsy cohort (dose levels 3.2-600 mg). While NSCLC (n = 8), clear cell RCC (n = 6), melanoma (n = 2), and bladder (n = 2) were represented, less immunogenic tumor types predominated. The median number of prior regimens for metastatic disease was 2 (range 0-9); 4 pts had received prior checkpoint inhibitors. As of 11 Jan 2016, no DLTs, G4/5 AEs attributed to study treatment, or AEs leading to treatment discontinuation were reported. The majority of treatment-related AEs were G1 in severity; 4 related G3 events (autoimmune hepatitis responsive to steroids, worsening dyspnea in a pt with malignant pleural effusions, hypertension, and fatigue) were reported. At doses ?40 mg q3w, PK was linear and sustained peripheral blood OX40 receptor saturation was achieved. Tumor pharmacodynamic (PD) biomarker modulation supportive of the mechanism of action was observed in a subset of pts. Eleven of 70 pts (16%) have been treated with MOXR0916 for > 6 months (?9 cycles) with a best response of stable disease per RECIST v1.1. Updated clinical data will be presented. Conclusions: In a heterogeneous, refractory population, MOXR0916 was well-tolerated at all doses evaluated. The recommended dose and schedule based on PK and OX40 receptor saturation is 300 mg q3w. Tumor PD modulation and evidence of prolonged stable disease support the ongoing expansion phase to evaluate anti-tumor activity in select indications and Phase Ib trial in combination with atezolizumab (anti-PD-L1). Citation Format: Aaron R. Hansen, Jeffrey R. Infante, Grant McArthur, Michael S. Gordon, Alexander M. Lesokhin, Ann-Lee Stayner, Todd M. Bauer, Shahneen Sandhu, Frank Tsai, Alexandra Snyder, Deepa S. Subramaniam, Jeong Kim, Eric Stefanich, Chi-Chung Li, Jane Ruppel, Maria Anderson, Houston Gilbert, Bruce McCall, Mahrukh A. Huseni, Ina Rhee, Michael Pishvaian. A first-in-human phase I dose escalation study of the OX40 agonist MOXR0916 in patients with refractory solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT097.
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) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».