Abstract B045: Ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in combination with low dose gemcitabine in patients with solid tumors with DNA damage response (DDR) aberrations: Preclinical and Phase 1b results
Notice bibliographique
Résumé
Abstract Background: Antitumor activity and good tolerability of camonsertib (cam) monotherapy in patients (pts) with recurrent solid tumors was previously reported. Preclinical data showed that cam-related tumor cell death is potentiated by the replication stress-inducing agent gemcitabine (gem) even at low doses, resulting in synergistic combination activity. We evaluated safety/tolerability and efficacy of cam+gem in this Ph1b trial (TRESR; NCT04497116). Methods: A tumor xenograft (Granta-519; ATM loss of function) was tested with a range of cam+gem doses. Pts >18yr, ECOG 0-1, with advanced solid tumors with deleterious DDR alterations were enrolled. Cam (80-120mg) + de-escalating gem doses (1000-100mg/m2) were given over 21- or 28-day (d) cycles (cam d1-2/3 and d8-9/10 or d15-16/17; gem d1 and d8 or d15). Dose decisions followed BOIN methodology. Endpoints were safety/tolerability, recommended Ph2 dose (RP2D), response rate (RECIST v1.1, CA-125 [GCIG], or PSA [PCWG3]), clinical benefit rate (CBR; response or treatment [Tx] duration ≥16 weeks [w] without progression), ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency ≥50%), and cam PK. Replication stress markers were analyzed in surrogate normal tissue. Results: In a tumor xenograft model, low doses of cam (1/3 of maximum tolerated dose [MTD]) and gem (1/20 of MTD) resulted in tumor regression not observed in single agent arms, with good tolerability. As of May 2023, 54 pts were treated with cam+gem in TRESR (ovarian [n=19], pancreatic [n=8], breast [n=6], other [n=21] tumors); enrollment genes included ATM (n=12), BRCA1 (n=18), BRCA2 (n=16), other (n=8). No drug-drug interactions were noted. RECIST v1.1 or CA-125 responses were observed in 5 pts (40 evaluable): 3 cPR, 1 uPR in pts with ovarian (n=2; 1 ATM, 1 BRCA1), endometrial (gPALB2), and breast (gBRCA1) cancers; 1 CA-125 response in a pt (ovarian/gBRCA1) with SD (on Tx 21w+). Four additional pts (uterine carcinosarcoma, ovarian, liver, lung) with SD were on Tx ≥6 months. CBR was 42.4% (14/33) in evaluable pts and 66.7% (8/12) in pts with gynecological cancers. MRR was 58% (7/12) in evaluable pts. Myelotoxicity, the most frequent Tx-related toxicity, improved with decreasing gem doses. Responses were maintained in the 3 pts with cPR following reductions to ≤200mg/m2 gem; the pts with the uPR and CA-125 responses started Tx at 200 and 100mg/m2 gem, respectively. Preliminary RP2D is 80mg cam (50% of monotherapy RP2D) + 400mg/m2 gem, 28d cycle (1w on/1w off). Related Grade 3+ neutropenia, anemia, and thrombocytopenia occurred in 44%, 11%, and 0% pts, respectively (n=9). Importantly, neutrophil nadir occurred in the 1w off Tx with quick rebound, alleviating the need for dose modifications. Conclusion: The synergy of low doses of cam+gem, demonstrated in preclinical studies, was confirmed in the clinical setting. A safe and tolerable dose and schedule of the combination was identified. The antitumor efficacy supports further development in pts with gynecological cancers; evaluation at RP2D is ongoing. Citation Format: Ezra Rosen, Timothy A Yap, Elisa Fontana, Elizabeth K Lee, Devalingam Mahalingam, Martin Højgaard, Niharika B Mettu, Gregory M Cote, Ruth Plummer, Ian M Silverman, Joseph D Schonhoft, Emeline Bacque, Adrian J Fretland, Gabriela Gomez, Danielle Ulanet, Kezhen Fei, Julia Yang, Maria Koehler, Anne Roulston, Li Li, Michal Zimmermann, Benedito A Carneiro, Stephanie Lheureux. Ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in combination with low dose gemcitabine in patients with solid tumors with DNA damage response (DDR) aberrations: Preclinical and Phase 1b results [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B045.
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 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,001 |
| 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 ».