First-in-Human, Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of RO5126766, a First-in-Class Dual MEK/RAF Inhibitor in Patients with Solid Tumors
- 30 August 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 18 (17), 4806-4819
- https://doi.org/10.1158/1078-0432.ccr-12-0742
Abstract
This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766. Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation was completed using 2 intermittent dosing schedules [7 days on treatment followed by 7 days off (7on/7off); 4 days on treatment followed by 3 days off (4on/3off)]. Fifty-two patients received RO5126766 at doses of 0.1 to 2.7 mg once daily, 2.7 to 4.0 mg (4 on/3 off), or 2.7 to 5.0 mg (7 on/7 off). The most common DLTs were elevated creatine phosphokinase (CPK) and blurred vision. The MTD for each dosing schedule was 2.25 mg once daily, 4.0 mg (4 on/3 off), and 2.7 mg (7 on/7 off). The dose/schedule recommended for phase II (RP2D) investigation was 2.7 mg (4 on/3 off). Frequent adverse events included rash-related disorders (94.2%), elevated CPK (55.8%), and diarrhea (51.9%). C(max) occurred 1 to 2 hours after dosing and mean terminal half-life was approximately 60 hours. Pharmacodynamic changes included reduced ERK phosphorylation, an increase in apoptosis in tumor tissue, and a reduction in fluorodeoxyglucose (FDG) uptake after 15 days of dosing. Three partial responses were seen: two in BRAF-mutant melanoma tumors and one in an NRAS-mutant melanoma. This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types.Keywords
Other Versions
This publication has 33 references indexed in Scilit:
- Improved Survival with Vemurafenib in Melanoma with BRAF V600E MutationNew England Journal of Medicine, 2011
- Multi-Institutional Phase II Study of Selumetinib in Patients With Metastatic Biliary CancersJournal of Clinical Oncology, 2011
- Phase II Study of the Mitogen-Activated Protein Kinase 1/2 Inhibitor Selumetinib in Patients With Advanced Hepatocellular CarcinomaJournal of Clinical Oncology, 2011
- Amplification of the Driving Oncogene, KRAS or BRAF , Underpins Acquired Resistance to MEK1/2 Inhibitors in Colorectal Cancer CellsScience Signaling, 2011
- Inhibition of Mutated, Activated BRAF in Metastatic MelanomaNew England Journal of Medicine, 2010
- Regulation of human myoblast differentiation by PEBP4EMBO Reports, 2009
- Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced CancersJournal of Clinical Oncology, 2008
- Mutations of the BRAF gene in human cancerNature, 2002
- New Guidelines to Evaluate the Response to Treatment in Solid TumorsJNCI Journal of the National Cancer Institute, 2000
- Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendationsEuropean Journal Of Cancer, 1999