Entry Detail
| General information | |
| Database: | DB00149 |
| Objective: | to define the maximum tolerated dose and recommendedphase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. |
| Authors: | Infante JR, et al |
| Title: | Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 doseescalation trial. |
| Journal: | Lancet Oncol |
| Year: | 2012 |
| PMID: | 22805291 |
| Trial Design | |
| Clinical Trial Id: | NCT00687622 |
| Agent: | trametinib |
| Target: | MEK2 Dual specificity mitogenactivated protein kinase kinase 1 |
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a phase I doseescalation trial |
| Key Patients Feature: | patients with advanced solid tumours and adequate organ function (median age 58.5 years, range 1992). |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommendedphase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. |
| Primary End Point: | maximum tolerated dose and recommendedphase 2 dose and safety, pharmacokinetics, pharmacodynamics, and response rate |
| Secondary End Point: | NA |
| Patients Number: | 206 |
| Trial Results | |
| DLT_MTD: | Doselimiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The maximum tolerated dose was 3 mg once daily and the recommendedphase 2 dose was 2 mg a day. |
| Objective Response Rate: | Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most common treatmentrelated adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. |
| Conclusions: | The recommendedphase 2 dose of 2 mg trametinib once a day is tolerable, with manageable sideeffects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. |