Multicenter Phase I Trial of the Mitogen-Activated Protein Kinase 1/2 Inhibitor BAY 86-9766 in Patients with Advanced Cancer

Abstract

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors.Experimental Design: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes.Results: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life $12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetatestimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy.Conclusion: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types.

A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer

“…The baseline demographics and disease characteristics of the non-HCC population were broadly consistent with a previous phase I study of refametinib monotherapy (14), although the HCC population comprised slightly more males. Only HCC patients with Child-Pugh A status were enrolled to ensure patients had stable liver function, similar to previous sorafenib trials (22,23).…”

“…Lack of toxicity in cohort 2A (refametinib 5 mg twice daily plus sorafenib 400 mg twice daily) led to escalation with sorafenib 400 mg twice daily as the backbone. The MTD was determined to be refametinib 50 mg twice daily in combination with sorafenib 400 mg twice daily, consistent with the phase I refametinib monotherapy study (14). Overall, daily oral dosing of refametinib plus sorafenib was well tolerated, up to and including at the MTD, with indications of clinical activity, consistent with the phase I study (14).…”

“…Refametinib (BAY 86-9766/RDEA119; Bayer Pharma AG) is a selective, orally available, potent, allosteric (non-adenosine triphosphate competitive) inhibitor of MEK1/2 (13) that has shown activity in multiple tumor types, including colorectal cancer (14) and preclinical models of hepatocellular carcinoma (HCC; ref. 15).…”

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

“…A similar targeted approach is being taken with the MEK-inhibitor refametinib (BAY 86-9766) in Ras-mutated HCC. Refametinib, a highly selective and potent small molecule allosteric (non-ATP-competitive) inhibitor of MEK 1 and MEK 2, showed potent single agent antitumor activity and acted synergistically in combination with sorafenib in preclinical HCC models, albeit with potential application for only a small subgroup of HCC patients [89][90][91] . Refa- …”

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

“…Numerous other early phase clinical trials have reported modulation of pERK in surrogate and tumour tissues following administration of MEK inhibitors [13][14][15]20]. However, differences in assays, tissues and time points used make direct comparisons problematic.…”