Trial in progress: A phase I study evaluating the safety of cirtuvivint (CIRT) as monotherapy and in combination with ASTX727 in patients with myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML)
Notice bibliographique
Résumé
Abstract Background and Signficance Patients with relapsed and/or refractory (R/R) MDS or AML have poor outcomes. Outcomes after resistance to venetoclax-based therapy are particularly poor with a median OS of 2.5 months independent of the type of salvage therapy used (Maiti et al., Haematologica 2020). Cirtuvivint (CIRT; SM08502) is an oral, potent inhibitor of the CLK and DYRK kinase families and modulates pre-mRNA splicing by inhibiting the phosphorylation of serine/arginine-rich splicing factors. This trial proposal is based on in vitro and in vivo preclinical data showing that SM08502 (CIRT) overcomes venetoclax resistance and synergizes with venetoclax by impairing X-linked inhibitor of apoptosis protein (XIAP) and a variety of splicing-dependent kinases (Wang et al., Cancer Cell 2023). CIRT has been evaluated in a phase I study in solid tumors and demonstrated potential therapeutic benefit (Scott et al., Ann Oncol. 2022). Methods Study design: This is a phase I, open-label, multi-center investigator-initiated Cancer Therapy Evaluation Program (CTEP) study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and recommended phase 2 dose (RP2D) of CIRT as monotherapy and in combination with ASTX727, a fixed-dose combination of oral decitabine and cedazuridine (NCT06484062). Treatment will be administered in cycles of 28 days. CIRT will be administered orally as monotherapy at different dose levels on a 5-day-on/2-day-off per week schedule (cohort I), or a 2-day-on/5-day-off per week schedule (cohort II). The RP2D determined from cohorts I and II will inform CIRT dosing for cohort III, in which ASTX727 will be administered days 1-5 of each cycle in combination with CIRT. Patients will undergo safety monitoring, including blood sample collection and bone marrow aspiration, at baseline and during treatment. Participants Adult patients with R/R AML or R/R MDS (both eligible for cohorts I and II) or untreated higher-risk MDS (cohort III), Eastern Cooperative Oncology Group performance status ≤ 3, and adequate organ function will be eligible. Patients must not have received prior treatment with CIRT or similar agents. Primary Objective The primary objective is to determine the RP2D of CIRT as monotherapy and in combination with ASTX727. Secondary Objectives Secondary objectives include assessing safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy. Correlative studies investigating biomarkers of response and RNA splicing patterns are also integral to this trial. Statistical methods The study uses a 3+3 dose escalation design. Determination of the RP2D will consider safety and tolerability data after the end of the DLT period, pharmacokinetic/pharmacodynamic data, and preliminary efficacy data from both cohorts I and II. A minimum of 6 and a maximum of 18 patients will be enrolled in each cohort for a total of 18-54 patients. The planned accrual rate is approximately 1-2 patient(s) per month for a total enrollment period of about 36 months. The RP2D determined will inform CIRT dosing for cohort III. Conclusions This phase I trial will establish the safety and RP2D for CIRT as monotherapy in R/R AML or R/R MDS (cohort I and II) and in combination with ASTX727 for untreated higher-risk MDS (cohort III). The trial is actively recruiting and aims to inform future phase II studies.
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 | 0,003 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,002 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,002 |
| Communication savante | 0,002 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,002 | 0,005 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,002 |
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 ».