Clinical pharmacokinetics of bdtx-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies in MasterKey-01 study
| Autor: | Rachel Humphrey, Alison M. Schram, Danny Nguyen, David S. Hong, Karsten Witt, Erika Hamilton, Leticia Tarilonte, Nigel J. Waters, Jasgit C. Sachdev, Shekeab Jauhari, Pasi A. Jänne, Manish R. Patel, Viola W. Zhu, Patricia LoRusso, Jordi Rodon Ahnert |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 39:3097-3097 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | 3097 Background: Allosteric oncogenic mutations occur outside the canonical ATP-binding site of EGFR and HER2, and there are no approved therapies that target such mutations. BDTX-189 is a potent, selective, irreversible inhibitor of 48 allosteric EGFR and HER2 mutant variants under clinical evaluation in the ongoing MasterKey-01 trial (NCT04209465). BDTX-189 was designed to rapidly and irreversibly occupy the active site of targeted ErbB mutants, leading to sustained pharmacodynamic (PD) effects, and with selectivity over EGFR-WT in order to minimize EGFR-WT mediated toxicities. The pharmacokinetic (PK) profile was designed for rapid absorption and fast elimination to maintain target occupancy while minimizing prolonged drug exposure that could contribute to off-target associated toxicities. Methods: In MasterKey-01, BDTX-189 was administered orally once daily in continuous 21-day cycles, taken fasted. Dose escalation included cohorts of 1-2 patients receiving doses between 25 and 200 mg QD followed by 5-7 patients receiving 400 mg, 800 mg, or 1,200 mg QD fasted. The possible effects of a high fat meal on the PK of BDTX-189 were assessed in a subset of patients receiving single doses of 400 mg BDTX-189 fasted and immediately after a high-fat breakfast in a randomized crossover fashion with 3 days between doses. In addition, a dose escalation cohort investigating administration of BDTX-189 non-fasted was enrolled at 800 mg QD. Serial blood samples for analysis of plasma BDTX-189 concentrations were collected after each dose on C1D1 and C1D15. BDTX-189 levels were determined using LC-MS, and data analyzed using non-compartmental methods. Results: After single and multiple doses, BDTX-189 was rapidly absorbed (median tmax 1-2 h), with an elimination t1/2 of 2-6 h. Dose-dependent increases in exposure from 200 to 800 mg QD fasted were observed, with no apparent accumulation or decline in exposures observed at steady-state. Administration of BDTX-189 with a high-fat meal increased AUC approximately 1.7-fold with minimal effect on Cmax, relative to administration in the fasted state. At 800 mg QD, mean AUC was similar in the non-fasting state relative to fasting and was within the target efficacious range defined by mouse models harboring allo-ErbB mutated tumors. Median tmax and t1/2 values were similar after administration in the non-fasted and fasted states. Conclusions: BDTX-189 demonstrated rapid absorption and a short PK half-life consistent with the desired PK/PD profile, with exposures in the efficacious target range based on preclinical data. The pilot high fat food-effect data and non-fasting QD dosing regimen show similar or improved systemic exposure relative to dosing in the fasted state. The MasterKey-01 trial is ongoing, including refinement of the dosing regimen and identification of the recommended phase 2 dose. Clinical trial information: NCT04209465. |
| Databáze: | OpenAIRE |
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