Abstract | PURPOSE: 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.
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Authors | Suzanne Leijen, Mark R Middleton, Patricia Tresca, Françoise Kraeber-Bodéré, Veronique Dieras, Max E Scheulen, Avinash Gupta, Vanesa Lopez-Valverde, Zhi-Xin Xu, Ruediger Rueger, Jean J L Tessier, Eliezer Shochat, Steve Blotner, Valerie Meresse Naegelen, Jan H M Schellens, Wilfried Ernst Erich Eberhardt |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 18
Issue 17
Pg. 4794-805
(Sep 01 2012)
ISSN: 1557-3265 [Electronic] United States |
PMID | 22767668
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2012 AACR. |
Chemical References |
- Benzamides
- CH 4987655
- Oxazines
- Protein Kinase Inhibitors
- MAP Kinase Kinase Kinases
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Topics |
- Administration, Oral
- Adult
- Aged
- Benzamides
(administration & dosage, adverse effects, pharmacokinetics)
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Female
- Humans
- MAP Kinase Kinase Kinases
(antagonists & inhibitors, metabolism)
- Male
- Maximum Tolerated Dose
- Middle Aged
- Neoplasm Staging
- Neoplasms
(drug therapy, pathology)
- Oxazines
(administration & dosage, adverse effects, pharmacokinetics)
- Protein Kinase Inhibitors
(administration & dosage, adverse effects, pharmacokinetics)
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