Abstract LB104: Dose-Finding/Expansion Phase Ib Study to Evaluate the Safety and Activity of BET Inhibitor RO6870810 (RO) and Atezolizumab (A) in Patients (pts) with Advanced Ovarian Cancer (OC) or Triple Negative Breast Cancer (TNBC)
Notice bibliographique
Résumé
Abstract Background: Transcriptional activation of c-MYC through bromodomain and extra-terminal (BET) proteins contributes to the malignant phenotype of OC and TNBC. RO is a novel thienodiazepine, small molecule, non-covalent inhibitor of the BET family of bromodomains. BET inhibition may also play a role in immune modulation via downregulation of CD47 and PD-L1. We hypothesized that RO may enhance the clinical potential of A. We report results of a phase 1b study of RO in combination with A in advanced OC and TNBC (NCT03292172). Methods: Patients with advanced OC or TNBC were eligible. In the dose escalation part, pts received subcutaneous escalating doses of RO (0.30, 0.45, 0.65 mg/kg) on days 1 - 14 of 21-day cycles in combination with A at 1200 mg IV on Day 1 of each cycle. In the expansion part, pts received RO at 0.45 mg/kg. Primary objectives were safety, tolerability and preliminary clinical activity of the combination. Results: Between Nov 2017 and Dec 2018, a total of 36 pts were enrolled, 27 pts in the dose escalation and 9 pts in the expansion part at 6 sites in the US, Canada, Denmark and Australia. The median age was 53 (34 - 72) years. 99 total cycles were completed, with a median of 2 (1-14) cycles per pt. During dose escalation, one pt at 0.65 mg/kg + A experienced a DLT of Grade 3 febrile neutropenia. Grade ≥ 3 treatment emergent AEs in ≥ 5% of all pts were immune-related AEs (irAEs) associated with laboratory findings suggestive of secondary hemophagocytic lymphohistiocytosis (HLH), anemia and hyponatremia (11.1% each), abdominal pain, fatigue and small intestinal obstruction (8.3% each), thrombocytopenia, ALT increased and hyperglycemia (5.6% each). Organ toxicities associated with the 4 cases of suspected HLH included fever and febrile neutropenia, myocarditis, encephalitis and pneumonitis; there was no clear correlation between RO exposure and these events. irAEs were observed in an additional 4 pts. AEs leading to treatment discontinuation were reported in 22.2% of pts, with suspected HLH being the most common AE (11.1%). A total of 15 deaths were reported in the study: 9 deaths due to progressive disease, and 6 deaths reported during long-term follow-up where the cause of death was reported as unknown. Two PRs were noted; one each at 0.30 mg/kg + A and at 0.45 mg/kg + A. 15 pts had SD and 14 pts had PD as best response. Median duration of disease control was 93 (95% CI 51-178) days. Response assessment of 5 pts was missing. Conclusions: While suspected HLH/HLH is rare for RO or A given as monotherapy, the safety profile of the combination was considered unacceptable as noted by the high frequency and severity of irAEs including suspected HLH. A limited anti-tumor activity was observed with PR as best overall response in 2 pts. The trial was terminated early due to the unfavorable risk-benefit profile. Citation Format: Stephanie Lheureux, Iben Spangaard, Erika Hamilton, George Au-Yeung, Debra Richardson, Mark DeMario, Emily Labriola-Tompkins, Barbara Brennan, Eveline Nueesch, Evelyne Chesne, Izolda Franjkovic, Katharina Lechner, Martin Kornacker, Geoffrey I. Shapiro. Dose-Finding/Expansion Phase Ib Study to Evaluate the Safety and Activity of BET Inhibitor RO6870810 (RO) and Atezolizumab (A) in Patients (pts) with Advanced Ovarian Cancer (OC) or Triple Negative Breast Cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB104.
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 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| 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 | 0,004 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,002 |
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 ».