Abstract B49: GRN1005 phase I studies: Final results.
Notice bibliographique
Résumé
Abstract Background: Treatment of brain tumors is an unmet medical need due to the inability of most anti-cancer agents to effectively cross the blood brain barrier (BBB). GRN1005 (formerly ANG1005) is a peptide-drug conjugate (PDC) consisting of three molecules of paclitaxel covalently linked to a proprietary 19-amino acid peptide (AngioPep-2) that targets the low-density lipoprotein receptor-related protein 1 (LRP-1), which is expressed on the surface of the BBB and on cells of various tumor types. Studies have shown that GRN1005 is capable of crossing the BBB by receptor-mediated transcytosis via LRP-1. Once in the brain, GRN1005 gains entry into tumor cells by binding to LRP-1 on the tumor cells. Objectives: GRN1005 is investigated as therapy for patients (pts.) with intra-cranial tumors, including malignant glioma and brain metastases (mets), in 2 phase I studies. The primary objectives of the studies were to determine the maximum tolerated dose (MTD) and to examine the safety and tolerability profile of GRN1005. Secondary objectives included tumor response, pharmacokinetics, and immunogenicity. Methods: Two phase I, multi-center, sequential cohort, dose escalation studies have been conducted with GRN1005 administered IV at doses from 30 to 700 mg/m2 once every 3 weeks (q3w); 1 cycle is q3w. Study ANG1005-CLN-01 (n = 63) was in pts. with primary brain tumors and Study ANG1005-CLN-02 (n=56) was in pts. with advanced solid tumors (breast, lung, others) in which most had brain mets. Results: The phase I studies have been completed and GRN1005 at 650 mg/m2 q3w was identified as the MTD in each of the studies. At MTD, the dose-limiting toxicity (DLT) was neutropenia. The incidence of CTCAE Grade 4 neutropenia was 63% and was of short duration; febrile neutropenia occurred in 3 pts. (8%). Other AEs included peripheral neuropathy (5/38 [13%] Grade 2 and 3/38 [8%] Grade 3) and thrombocytopenia (25/38 [68%] Grades 1–3 and 1/38 [3%] Grade 4). There were 4 cases of Grade 3 infusion reactions at MTD (11%). Across all doses, the overall incidence of infusion reactions of any grade is 13% (15/119). No pre-medication was required with GRN1005 infusion in the phase I studies. Liver toxicity was not observed. There was no evidence of CNS toxicity as measured by neurocognitive testing and neurological examinations; and there was no evidence of anti-drug antibody production. Clinical activity in the phase I studies was observed with GRN1005 therapy in both studies. In Study ANG1005-CLN-01, 1 (6%; n=18) pt. achieved a partial response (PR) at MTD. Additionally, 1 pt. out of 3 in the 700 mg/m2 cohort achieved a complete response and 1 pt. out of 4 in the 420 mg/m2 cohort achieved a PR. In Study ANG1005-CLN-02, 4 of 20 (20%) pts. treated at MTD achieved an overall partial response (PR); some pts. had intra-cranial and extra-cranial lesion responses, despite prior taxane failures. A substudy showed GRN1005 and free paclitaxel concentrations in excised primary brain tumors. Conclusions: In the GRN1005 phase I studies, single agent clinical activity was observed in pts. with primary brain tumors and in pts. with solid tumor brain metastases, including prior taxane failures; extra-cranial responses were observed along with intra-cranial responses. GRN1005's MTD is 650 mg/m2 q3w, and neutropenia was the DLT. Given the clinical activity and safety/tolerability observed in phase I, GRN1005 as therapy for pts. with intra-cranial tumors is being further investigated in phase 2 studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B49.
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 | 0,000 | 0,000 |
| 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 | 0,000 |
| 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 ».