دورية أكاديمية
Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma.
| العنوان: | Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma. |
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| المؤلفون: | Rasco DW; South Texas Accelerated Research Therapeutics, LLC, San Antonio, TX, USA., Medina T; University of Colorado Cancer Center, Aurora, CO, USA., Corrie P; Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Pavlick AC; Laura & Isaac Perlmutter Cancer Center at NYU Langone, New York, NY, USA., Middleton MR; Department of Oncology, NIHR Biomedical Research Centre, Oxford, UK., Lorigan P; The Christie NHS Foundation Trust and Division of Cancer Sciences, University of Manchester, Manchester, UK., Hebert C; Bristol Haematology and Oncology Centre, Bristol, UK., Plummer R; The Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, UK., Larkin J; The Royal Marsden Hospital, London, UK., Agarwala SS; St. Luke's Cancer Center and Temple University, Easton, PA, USA., Daud AI; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA., Qiu J; Day One Biopharmaceuticals, 2000 Sierra Point Parkway, Suite 501, Brisbane, CA, 94005, USA., Bozon V; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA., Kneissl M; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA., Barry E; Day One Biopharmaceuticals, 2000 Sierra Point Parkway, Suite 501, Brisbane, CA, 94005, USA. elly.barry@dayonebio.com., Olszanski AJ; Fox Chase Cancer Center, Philadelphia, PA, USA. |
| المصدر: | Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2023 Jul; Vol. 92 (1), pp. 15-28. Date of Electronic Publication: 2023 May 23. |
| نوع المنشور: | Clinical Trial, Phase I; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7806519 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0843 (Electronic) Linking ISSN: 03445704 NLM ISO Abbreviation: Cancer Chemother Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Berlin : Springer Verlag Original Publication: Berlin, New York, Springer International. |
| مواضيع طبية MeSH: | Neoplasms*/pathology , Melanoma*/pathology , Skin Neoplasms*/pathology , Neoplasms, Second Primary*, Adult ; Humans ; Proto-Oncogene Proteins B-raf/genetics ; Protein Kinase Inhibitors ; Mitogen-Activated Protein Kinase Kinases ; Maximum Tolerated Dose |
| مستخلص: | Purpose: Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib. Methods: This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics. Results: Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg. Conclusions: The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings. Gov Identifier: NCT01425008. (© 2023. The Author(s).) |
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| فهرسة مساهمة: | Keywords: BRAF; Melanoma; Pan-RAF inhibitor; Phase 1; Tovorafenib |
| سلسلة جزيئية: | ClinicalTrials.gov NCT01425008 |
| المشرفين على المادة: | EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) 0 (Protein Kinase Inhibitors) EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) |
| تواريخ الأحداث: | Date Created: 20230523 Date Completed: 20230614 Latest Revision: 20231127 |
| رمز التحديث: | 20240829 |
| مُعرف محوري في PubMed: | PMC10261210 |
| DOI: | 10.1007/s00280-023-04544-5 |
| PMID: | 37219686 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1432-0843 |
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| DOI: | 10.1007/s00280-023-04544-5 |