Abstract PO-005: Phase 1/2 study of Ad/PNP with fludarabine for the treatment of head & neck squamous cell carcinoma (HNSCC)
Notice bibliographique
Résumé
Abstract The project pursues clinical testing of a gene-based treatment for refractory malignancy of the head and neck. Background We are evaluating intratumoral nucleoside cleavage by E. coli purine nucleoside phosphorylase (PNP) as an experimental therapy for refractory solid tumors. The approach requires delivery of PNP transgene to tumor parenchyma followed by prodrug administration, and provides “bystander” killing by a very potent purine antimetabolite (F-Ade) generated intratumorally. F-Ade is 1,000-times more potent than fluorouracil, the chemotherapeutic produced by cytosine deaminase (CD; a first-generation construct used for tumor sensitization). PNP/F-Ade has been found to be superior to CD/fluorouracil by several laboratories. In a Phase 1 study (Rosenthal et al., Ann. Oncol.), antitumor activity was observed after IT injections of a recombinant adenovirus encoding PNP (Ad/PNP), followed by IV fludarabine phosphate (F-araAMP, a prodrug converted by PNP to F-Ade). Methods Patients in the present trial have RECIST 1.1 measurable HNSCC amenable to local injection and no other palliative treatment options. A single-arm protocol is being used to evaluate safety of repeat cycles of Ad/PNP and F-araAMP. Ad/PNP is injected intratumorally twice on Day 1 and once on Day 2, followed by infusion of F-araAMP on Days 3, 4, and 5 every 4 weeks for up to 5 cycles. Results Eight patients have been enrolled to date. There have been no dose limiting toxicities, no serious adverse events (SAEs) definitively attributable to treatment, and no AEs above grade 3 severity. Up to five cycles of Ad/PNP treatment have been administered without limiting sequelae. Intratumoral expression of PNP transgene by RT-PCR has been established in treated tumors. Other correlative endpoints are in process and will be discussed. One patient exhibited tumor volume reduction by approximately 21% (as judged by CT imaging) and did not increase during five months of treatment, consistent with clinically stable disease. Two other patients completed three months of Ad/PNP with stable disease by RECIST criteria during the treatment period. Another patient’s tumor (largest dimension 3.1 cm) demonstrated 25% decrease after one treatment cycle. Challenges have included: 1) complexity of distribution of agent into large volume tumors (e.g., >100 ml) with small volume of Ad/PNP, and 2) acute swelling of tumor tissue following intratumoral virus injection in two patients, consistent with inflammatory response and/or disease progression. Conclusions Administration of Ad/PNP is safe and feasible. Injections of large volume tumors remains a challenge. The strategy is also being considered for earlier-stage HNSCC with less tumor burden, including a role similar to neoadjuvant or cytoreductive radiotherapy in combination with checkpoint blockade inhibition. A muti-center trial is planned to define MTD and feasibility in smaller tumors. Citation Format: A. Dimitrios Colevas, Eric J. Sorscher, William B. Parker, Roan Courtney Raymundo, Jeong S. Hong, Regina Rab, Camilo Henao, Nikki Schmitt, Madison Stallings, Kelly T. McKee, Eben Rosenthal, Joseph Curry. Phase 1/2 study of Ad/PNP with fludarabine for the treatment of head & neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-005.
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 | 0,002 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| 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 ».