Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors
| Autor: | Renee Iacona, Alan Swaisland, José Baselga, Paul Elvin, Andrés Cervantes, Herbert Hurwitz, Esther Casado, Klaas Hoekman, Duncan I. Jodrell, Erika Martinelli, Josep Tabernero, Paul Hamberg, Isabel Chirivella |
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| Přispěvatelé: | Baselga, J, Cervantes, A, Martinelli, Erika, Chirivella, I, Hoekman, K, Hurwitz, Hi, Jodrell, Di, Hamberg, P, Casado, E, Elvin, P, Swaisland, A, Iacona, R, Tabernero, J., Medical oncology, CCA - Innovative therapy |
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Cancer Research Drug-Related Side Effects and Adverse Reactions Maximum Tolerated Dose Administration Oral Phases of clinical research Antineoplastic Agents Neutropenia Pharmacology Drug Administration Schedule Young Adult Pharmacokinetics Neoplasms medicine Humans Benzodioxoles Dosing Protein Kinase Inhibitors Aged Dose-Response Relationship Drug business.industry Area under the curve Middle Aged medicine.disease Enzyme Activation Treatment Outcome src-Family Kinases Oncology Tolerability Disease Progression Quinazolines Female Biological half-life business Febrile neutropenia |
| Zdroj: | Baselga, J, Cervantes, A, Martinelli, E, Chirivella, I, Hoekman, K, Hurwitz, H I, Jodrell, D I, Hamberg, P, Casado, E, Elvin, P, Swaisland, A, Iacona, R & Tabernero, J 2010, ' Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors ', Clinical Cancer Research, vol. 16, no. 19, pp. 4876-4883 . https://doi.org/10.1158/1078-0432.CCR-10-0748 Clinical Cancer Research, 16(19), 4876-4883. American Association for Cancer Research Inc. |
| ISSN: | 1078-0432 |
| DOI: | 10.1158/1078-0432.CCR-10-0748 |
| Popis: | Purpose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors. Experimental Design: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing. Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours. Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d. Clin Cancer Res; 16(19); 4876–83. ©2010 AACR. |
| Databáze: | OpenAIRE |
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