| General information |
| Database: | DB00310 |
| Objective: | To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 869766, a selective, potent, orally available, smallmolecule allosteric inhibitor of mitogenactivated protein kinase 1/2 in patients with advanced solid tumors. |
| Authors: | weekes CD, et al |
| Title: | Multicenterphase I trial of the mitogenactivated protein kinase 1/2 inhibitor BAY 869766 in patients with advanced cancer. |
| Journal: | Clin Cancer Res. |
| Year: | 2013 |
| PMID: | 23434733 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | BAY 869766
|
| Target: | Dual specificity mitogenactivated protein kinase kinase
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | an openlabel, phase I trial |
| Key Patients Feature: | aged 18 years or older with a histologic or cytologic confirmed advanced nonhematologic cancer for which no proven effective therapy was available, ECOG performance status of 1 or less, and life expectancy of 12 weeks or more |
| Biomarker: | extracellular signalregulated kinase (ERK) phosphorylation |
| Biomark Analysis: | BAY 869766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetatestimulated peripheral blood leukocytes. An ocular melanoma specimen harbored a GNAQactivating mutation and exhibited reduced ERK phosphorylation in response to therapy. |
| Control Group Info: | single arm |
| Treatment Info: | BAY 869766 was administered orally daily in 28day courses, with doses escalated to establish the maximumtolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signalregulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. |
| Primary End Point: | safety of escalating doses to identify the maximumtolerated dose (MTD). |
| Secondary End Point: | single and multiple dose pharmacokinetics, evaluation of pharmacodynamic effects in peripheral blood and tumor biopsy specimens, and evaluation of safety and tolerability of the recommendedphase II dose (RP2D). |
| Patients Number: | 69 |
| Trial Results |
| DLT_MTD: | 20 patients at the MTD. The MTD was 100 mg given oncedaily or in two divided doses. BAY 869766 was welltolerated. The most common treatmentrelated toxicities were acneiform rash and gastrointestinal toxicity. |
| Objective Response Rate: | Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. |
| 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): | NA |
| Conclusions: | Thisphase I study showed that BAY 869766 was welltolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. |