Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors.
PURPOSE: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advan...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2012
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| _version_ | 1797073767005945856 |
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| author | Leijen, S Middleton, MR Tresca, P Kraeber-Bodéré, F Dieras, V Scheulen, M Gupta, A Lopez-Valverde, V Xu, Z Rueger, R Tessier, J Shochat, E Blotner, S Naegelen, V Schellens, J Eberhardt, W |
| author_facet | Leijen, S Middleton, MR Tresca, P Kraeber-Bodéré, F Dieras, V Scheulen, M Gupta, A Lopez-Valverde, V Xu, Z Rueger, R Tessier, J Shochat, E Blotner, S Naegelen, V Schellens, J Eberhardt, W |
| author_sort | Leijen, S |
| collection | OXFORD |
| description | PURPOSE: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. PATIENTS AND METHODS: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule. RESULTS: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC(50)). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15. CONCLUSION: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors. |
| first_indexed | 2024-03-06T23:26:45Z |
| format | Journal article |
| id | oxford-uuid:6a9e1511-fba6-4ed6-9b5e-dc52ed5a8a99 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:26:45Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:6a9e1511-fba6-4ed6-9b5e-dc52ed5a8a992022-03-26T18:58:43ZPhase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6a9e1511-fba6-4ed6-9b5e-dc52ed5a8a99EnglishSymplectic Elements at Oxford2012Leijen, SMiddleton, MRTresca, PKraeber-Bodéré, FDieras, VScheulen, MGupta, ALopez-Valverde, VXu, ZRueger, RTessier, JShochat, EBlotner, SNaegelen, VSchellens, JEberhardt, WPURPOSE: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. PATIENTS AND METHODS: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule. RESULTS: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC(50)). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15. CONCLUSION: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors. |
| spellingShingle | Leijen, S Middleton, MR Tresca, P Kraeber-Bodéré, F Dieras, V Scheulen, M Gupta, A Lopez-Valverde, V Xu, Z Rueger, R Tessier, J Shochat, E Blotner, S Naegelen, V Schellens, J Eberhardt, W Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. |
| title | Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. |
| title_full | Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. |
| title_fullStr | Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. |
| title_full_unstemmed | Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. |
| title_short | Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors. |
| title_sort | phase i dose escalation study of the safety pharmacokinetics and pharmacodynamics of the mek inhibitor ro4987655 ch4987655 in patients with advanced solid tumors |
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