التفاصيل البيبلوغرافية
| العنوان: |
First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors |
| المؤلفون: |
Howard L. Kaufman, Martin Stogniew, Joseph Aisner, Janice M. Mehnert, Joshua E. Allen, Ling Zheng, Bruce G. Haffty, Mark N. Stein, Tracie Saunders, Robert Aiken, Wolfgang Oster, Wafik S. El-Deiry, Nancy Chan, Yasmeen Beckett, Loma Rodriguez, Robert S. DiPaola, Jyoti Malhotra, Sherri Damare, Sioghan Dickerson, Ann W. Silk, Tina M. Mayer, Christian Gabel, Bangning Yu, Saltanat Najmi, Joseph R. Bertino, Rebecca A. Moss, Andrew Zloza |
| المصدر: |
Clin Cancer Res |
| سنة النشر: |
2016 |
| مصطلحات موضوعية: |
0301 basic medicine, Adult, Male, Cancer Research, medicine.medical_specialty, Pyridines, Cmax, Antineoplastic Agents, Pharmacology, Gastroenterology, Heterocyclic Compounds, 4 or More Rings, Article, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Prostate, Internal medicine, Neoplasms, medicine, Humans, Adverse effect, Aged, Dose-Response Relationship, Drug, business.industry, Receptors, Dopamine D2, Endometrial cancer, Antagonist, Imidazoles, Cancer, Middle Aged, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Pyrimidines, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Pharmacodynamics, Female, business |
| الوصف: |
Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163–9. ©2017 AACR. |
| تدمد: |
1557-3265 |
| الوصول الحر: |
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::acebeffd9ec3bcdcb71578c07b5290cbTest
https://pubmed.ncbi.nlm.nih.gov/28331050Test |
| حقوق: |
OPEN |
| رقم الانضمام: |
edsair.doi.dedup.....acebeffd9ec3bcdcb71578c07b5290cb |
| قاعدة البيانات: |
OpenAIRE |
