Sudocetaxel zendusortide (TH1902), a novel sortilin-receptor (SORT1)-targeting peptide-drug-conjugate (PDC) in patients (pts) with advanced solid tumors: Results from part 1 (dose-escalation) of a phase 1, open-label study.
Notice bibliographique
Résumé
3089 Background: SORT1 is expressed in a variety of tumors when compared to most healthy tissue. TH1902 is a first-in-class PDC targeting SORT1, that consists of 2 molecules of docetaxel attached to the TH19P01 peptide via a cleavable succinyl linker. Conjugating the short peptide with various anti-cancer agents allows for targeted delivery of payloads to the tumor. Here we report results from Part 1 of a FIH, multicenter, phase 1 study, designed to explore the safety, pharmacokinetics (PK) and efficacy of TH1902 in advanced solid tumors. Methods: Part 1 used a modified rapid intrapatient dose escalation design. A starting dose of 30 mg/m2 Q3W of TH1902 was used for the study based on the available pre-clinical data of TH1902 and the known safety profile of docetaxel. Eligibility criteria included pts with advanced solid tumors (all-comers) that have relapsed or are refractory to standard anticancer treatment. Pts had no limit on previous lines of therapy, and were required to have measurable disease by RECIST, expected survival of ≥3 months, ECOG 0-1, and adequate organ function. Pts were not required to be tested for SORT1 at entry. The primary objective of the study was to characterize the safety and tolerability of TH1902. The primary objective of Part 1 was to identify the maximum tolerated dose and the recommended dose for Part 2 (dose expansion). Additional objectives included the examination of the PK of TH1902 and free docetaxel, and outcomes as related to SORT1 expression. Results: As of April 2022, 18 pts were enrolled in Part 1 and included 6 ovarian, 1 endometrial, 1 cervical, 3 prostate, 3 ER+/Her2+ BC, 3 melanoma and 1 NSCLC. Pts received an average of 8 prior regimens (range: 3-20). All pts received at least 1 dose of study drug and were evaluated after the 1st cycle for a DLT. Dose levels between 30-420 mg/m2 Q3W were studied. Following safety observations among the 6 patients enrolled at the 420 mg/m2 dose level (Gr 3 neuropathy [n=2], Gr 4 neutropenia [n=2], Gr 3 ocular [n=1] and Gr 2 skin toxicities), the dose was reduced to 300 mg/m2. At the at 300 mg/m2 cohort, seven pts received a mean of 2.9 cycles. AEs (regardless of relatedness) occurred in all 7 (100%) pts, mostly Gr 1-2. One pt had Gr 3 worsening anemia (probably related) and Gr 3 abdominal pain/fistula (unrelated). AEs of interest were all Gr 1-2, and included: ocular (keratitis/dryness)=2 pts; GI (nausea/vomiting/diarrhea)=2 pts; neuropathy=2 pts; MSK (arthralgia/myalgia/extremity pain)=2 pts. In 15 evaluable pts in Part 1 clinical benefit was observed in 10 pts: 1 PR (prostate with 53% decrease in target lesion) and 9 SD. PK and SORT1 expression analyses are ongoing. Conclusions: Although biological activity has been observed, the optimal dosing regimen of TH1902 is currently under evaluation. Clinical trial information: NCT04706962 .
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) | 0,001 | 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 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 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 ».