Anti Tumor Activity Of Selinexor (KPT-330), A First-In-Class Oral Selective Inhibitor Of Nuclear Export (SINE) XPO1/CRM1 Antagonist In Patients (pts) With Relapsed / Refractory Multiple Myeloma (MM) Or Waldenstrom’s Macroglobulinemia (WM)
Notice bibliographique
Résumé
Background Exportin 1 (XPO1/CRM1) is overexpressed in MM and was identified as an essential protein for MM cell growth. The majority of Tumor Suppressor Proteins (TSP) are transported out of the nucleus exclusively by XPO1, leading to their inactivation. Selinexor (KPT-330) is a potent, selective oral inhibitor of XPO1 and shows potent anti myeloma activity in preclinical models. Methods Patients (pts) with advanced, relapsed/refractory MM or WM were dosed with oral Selinexor (8-10 doses / 4-week cycle) as part of a broad Phase 1 program (NCT 01607892) in advanced hematological malignancies. Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and tumor biopsies on selected patients were performed. Response evaluation was performed every cycle. All pts in this study had documented progressive disease on study entry and were relapsed/refractory to at least one proteasome inhibitor and one immunomodulating agent. Results 17 MM and 2 WM pts with median age 67yrs (range 50-75); ECOG PS 0/1: 6/13; median number of prior regimens: 5 [range 1-13], received Selinexor across 6 dose levels (3 to 30 mg/m2). Five patients experienced drug-related grade 3/4 Adverse Events (AEs), including thrombocytopenia without bleeding (n=4), neutropenia (n=4), impaired renal function (n=1), decreased WBC (n=1) and febrile neutropenia (n=1). The most common grade 1/2 toxicities are gastrointestinal (GI) including nausea (16/19; 84%), anorexia (11/19pts; 58%), vomiting (8/19; 42%), diarrhea (7/19pts; 37%), weight loss (4/19; 21%) and dysgeusia (4/19; 21%). Grade 1/2 study drug related fatigue was also observed in 10/19 or 53% of the patients. No grade ≥3 GI related AEs were observed. These side effects were well managed with supportive care. No clinically significant cumulative drug toxicities have been noted and patients have remained on therapy for >8 months (median duration on therapy 50 days, range 8-274 days). Two pts died during the study, one due to E.coli sepsis and the other due to renal dysfunction, both events deemed by treating investigators to be unrelated to study drug. PK analysis demonstrated total exposure increased with increasing dose, with no accumulation and without affecting half-life (5-7 hrs) or clearance of KPT-330. At 23 mg/m2, exposure (Cmax 289 ng/mL and AUC0-inf 2219 ng*h/mL) was comparable to anti tumor exposure observed in mice and dogs. Significant increases (2-20x) in leukocyte XPO1 mRNA levels (PDn marker) were observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA. Response was evaluable in 15 MM pts: Partial response (PR) in 1 pt (6.7%) at 35mg/m2, Minimal Response (MR) in 6 pts (40%) at doses of 16.8 to 30mg/m2, Stable Disease (SD) in 5 pts (33%) and Progressive Disease (PD) in 3 pts (20%). One MR and 1 SD were observed in the 2 WM pts. Evaluation of serial bone marrow samples from one patient confirms Selinexor-induced nuclear localization of multiple TSPs as well as reduction in CD138+ MM cells. Dose escalation is ongoing at 35 mg/m2 twice weekly. Conclusions Oral Selinexor treatment is generally well tolerated, with favorable PK and PDn properties. Prolonged disease control and responses are observed in heavily pretreated patients with progressive MM whose disease is relapsed or refractory to available agents. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Experimental use of Selinexor, a drug not yet approved. Baz: Celgene, Millennium, BMS, Novartis, Karyopharm, Sanofi: Research Funding. Reece: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding; Novartis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; BMS: Research Funding; Otsuka: Honoraria, Research Funding; Onyx: Consultancy. Siegel: Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau. Kuruvilla: Seattle Genetics : Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Karyopharm: Research Funding. Shacham: Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Rashal: Karyopharm Therapeutics Inc.: Employment, Equity Ownership. McCauley: Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin: Karyopharm Therapeutics Inc.: Employment, Equity Ownership. McCartney: Karyopharm Therapeutics Inc.: Employment, Equity Ownership. Landesman: Karyopharm Therapeutics: Employment, Equity Ownership, Patents & Royalties. Klebanov: Karyopharm Therapeutics: Employment, Equity Ownership. Pond: Osmozis : Consultancy. Kauffman: Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Mirza: Karyopharm Therapeutics Inc.: Consultancy, Equity Ownership.
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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 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 | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 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 ».