Safety, antitumor activity, and pharmacokinetics of dostarlimab, an anti-PD-1, in patients with advanced solid tumors: a dose–escalation phase 1 trial
| العنوان: | Safety, antitumor activity, and pharmacokinetics of dostarlimab, an anti-PD-1, in patients with advanced solid tumors: a dose–escalation phase 1 trial |
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| المؤلفون: | Drew W. Rasco, Amita Patnaik, Kristen McEachern, Sharon Lu, Wei Guo, Lisa Blaydorn, Murali Beeram, Ellie Im, Amy Mirabella, Jasgit C. Sachdev, Hadi Danaee, Glen J. Weiss |
| المصدر: | Cancer Chemotherapy and Pharmacology |
| بيانات النشر: | Springer Berlin Heidelberg, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Cancer Research, medicine.medical_specialty, Maximum Tolerated Dose, Programmed Cell Death 1 Receptor, Urology, Phases of clinical research, Toxicology, Antibodies, Monoclonal, Humanized, Programmed cell death receptor 1, Pharmacokinetics, Advanced cancer, Neoplasms, medicine, Dostarlimab, Humans, Pharmacology (medical), In patient, Dosing, Immune Checkpoint Inhibitors, Aged, Pharmacology, Antitumor activity, business.industry, Body Weight, Phase 1 clinical trial, Middle Aged, Drug class, Treatment Outcome, Oncology, TSR-042, Pharmacodynamics, Area Under Curve, Toxicity, Original Article, business |
| الوصف: | Purpose New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. Methods Part 1 featured a 3 + 3 weight-based dose–escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator’s decision, or death. Results The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed. Conclusions Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class. Trial registration: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016. |
| اللغة: | English |
| تدمد: | 1432-0843 0344-5704 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a01bdcc28b555d4d52481b0db48989ccTest http://europepmc.org/articles/PMC8739161Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a01bdcc28b555d4d52481b0db48989cc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14320843 03445704 |
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