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 cancers

Abstract

Purpose: To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer.

Patients and methods: In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations.

Results: Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated >or= 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for >or= 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles.

Conclusion: AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.

Fig 1

Immunostains of pre- and post-treatment melanoma specimens from the same patient. (A) Before dose, tumor cells are reactive to anti-pERK antibody (brown staining; magnification, ×100). (B) After dose, cells are unreactive to same anti-pERK antibody (magnification, ×100). (C) Before dose, variable nuclear Ki-67 labeling (approximately 30% positive nuclei; magnification, ×400). (D) After dose, marked reduction in nuclear Ki-67 labeling (< 1% positive nuclei; magnification, ×400)

Fig 2

Percent change from baseline at day 15 (± 7 days) in (A) tumor cell nuclei H-score for pERK and (B) proportion of tumor cell nuclei staining for Ki-67. Patients received 100 mg bid or 200 mg bid (denoted by *).

Fig 3

Best percent change from baseline in target lesion size for patients who have at least postbaseline efficacy assessment.