617 Combined histone deacetylase and PD-L1 inhibition is safe and efficacious for the treatment of virus-associated cancers: results of a phase II clinical trial
Notice bibliographique
Résumé
<h3>Background</h3> Valproate (VPA) is an orally available histone deacetylase (HDAC) inhibitor and avelumab is a therapeutic anti-PD-L1 monoclonal antibody. VPA is known to arrest the growth of transformed cells and has also been shown to enhance the efficacy of chemotherapy in virus-associated solid tumors (VAST) by increasing lytic viral gene expression. We hypothesized that combining VPA with avelumab may be an effective therapeutic strategy for the treatment of patients with VAST. <h3>Methods</h3> We designed a single-arm, basket phase II feasibility trial. Patients with EBER+ nasopharyngeal (n=12) or p16+ oropharyngeal (8), cervical (7), anal (6), penile (3) or vaginal (2) carcinoma were enrolled. Patients received oral VPA (target serum concentration ug/mL) with avelumab 10 mg/kg intravenously until progression of disease, or a maximum of two years’ duration. Objective response rate (ORR) was a co-primary endpoint with feasibility while safety, progression-free and overall survival (PFS/OS) were secondary outcomes under study. <h3>Results</h3> 39 patients were enrolled. Treatment was feasible; of 39 patients just two did not complete the pre-defined threshold of four treatment cycles. Approximately one-half of patients received first-line (metastatic) treatment, the remainder of patients had received ≥1 line(s) of therapy at the time of enrolment. ORR by RECIST 1.1 was 21% across the entire cohort; of interest, two of three patients with penile cancer achieved a sustained, partial response. Treatment responses were seen in all patient cohorts, except those with vaginal squamous cell carcinoma. All observed treatment responses have been durable in nature. For the all-patient analysis, median PFS and OS were 6.9 and 21.7 months, respectively. Treatment was well tolerated, with a safety profile consistent with that observed with PD-(L)1 blockade. We identified novel predictive biomarkers; the expression of galectin-9 on peripheral monocytes negatively correlated with efficacy, and increased serum IL8/IL18 and CD71+ erythrocyte precursor cells also predicted poor treatment outcomes. <h3>Conclusions</h3> We report feasibility, efficacy and safety results of a completed phase II trial combining HDAC and PD-L1 inhibition. Encouragingly, despite enrolling patients with prior therapy ORR were similar in this trial to those seen historically in untreated patients, and no new safety concerns were identified by combining HDAC inhibition with PD-L1 blockade. Ongoing biomarker analyses may be helpful in identifying patients for whom combination therapy could be considered. <h3>Acknowledgements</h3> The authors would like to acknowledge the support of the Alberta Cancer Foundation, as well as EMD Serono. Most importantly, the authors wish to thank the patients and their families who participated in this clinical trial. <h3>Trial Registration</h3> This clinical trial was registered with the National Institute of Health (NIH); clinical trial registration number NCT03357757. <h3>Ethics Approval</h3> This clinical trial was approved by the Health Research Ethics Board of Alberta (HREBA) Cancer Committee (approval number HREBA.CC-17-0374).
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 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 | 0,001 | 0,001 |
| 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 | 0,001 |
| 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 ».