Safety and preliminary clinical activity of JNJ-63898081 (JNJ-081), a PSMA and CD3 bispecific antibody, for the treatment of metastatic castrate-resistant prostate cancer (mCRPC).
Notice bibliographique
Résumé
279 Background: PSMA expression is increased in response to anti-androgen therapies and is a promising therapeutic target for the treatment of prostate cancer (PCa). JNJ-081 is a bispecific antibody with one arm binding PSMA on cancer cells and the other binding CD3 on T-cells to promote anti-tumor activity. Methods: This Phase 1 Dose Escalation Study evaluated JNJ-081 in mCRPC participants (pts) who progressed after novel androgen targeting therapy (eg, abiraterone, enzalutamide or apalutamide). Prior chemotherapy was permitted. JNJ-081 was administered initially by intravenous (IV) then by subcutaneous (SC) route. Dose escalation followed a continuous reassessment method based on a Bayesian regression model. The primary endpoint to determine the recommended phase 2 dose (RP2D) was based on safety. Pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary anti-tumor activity were also evaluated. Cytokine release syndrome (CRS) was graded by CTCAE V5. Results: As of 10 May 2021, 39 pts were dosed in 10 cohorts ranging from 0.1 µg/kg to 3 µg/kg IV and from 3 µg/kg to 60 µg/kg SC. Premedications included high dose corticosteroids. Step-up priming was implemented at higher SC doses. Most common treatment-emergent AEs were CRS (65%), fatigue (49%) and nausea (43%). 2 pts developed DLTs of Grade (G) 3 or G4 transaminases increased, 1 each at 30 µg/kg SC and priming with 10 µg/kg SC then 55 µg/kg SC, respectively. Both DLTs were in conjunction with or followed an episode of G2 CRS. SC route as well as step-up priming helped mitigate CRS and infusion-related reaction (IRR) during escalation to higher doses: at 3 µg/kg IV, 4 of 5 pts had G2 CRS or IRR; at 30 µg/kg SC, 3 of 4 pts had G2 CRS; priming with 10 µg/kg then 55 µg/kg SC, 4 of 5 pts had G2 CRS. Injection site reactions (G1 or G2) occurred in 24 of 26 pts treated via SC JNJ-081. No treatment related death was reported. Transient PSA decreases were observed at treatment doses greater than 30 µg/kg SC. Two subjects treated with 55 µg/kg had PSA decreases > 50%. No radiographic responses were observed. PK of JNJ-081 was linear over the dose range of 3-60 µg/kg following SC administration. SC bioavailability was approximately 25%. Anti-drug antibodies (ADA) were detected in 2 of 12 subjects treated by IV administration and 14 of 23 pts treated by SC administration. ADA resulted in loss of exposure in some SC pts. Intrapatient dose escalation in 3 pts did not overcome the reduced exposure after ADA seropositivity. Conclusions: JNJ-081 demonstrated transient decreases in PSA in mCRPC patients. Grade 2 CRS was observed at higher doses and was partially mitigated by SC and step-up dosing. ADA resulting in decreased exposure occurred in the majority of pts treated SC. PSMA remains a potential therapeutic target for T-cell redirection for the treatment of PCa. Clinical trial information: NCT03926013.
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 | 0,000 |
| 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 | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| 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 ».