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.

Conflict of interest statement

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Clive Morris, AstraZeneca (C); David Wilson, AstraZeneca (C); Lara Maloney, Array BioPharma Inc (C); Heidi Simmons, Array BioPharma Inc (C); Allison Marlow, Array BioPharma Inc (C); Kevin Litwiler, Array BioPharma Inc (C); Suzy Brown, Array BioPharma Inc (C); Gregory Poch, Array BioPharma Inc (C); Katie Kane, Array BioPharma Inc (C) Consultant or Advisory Role: Alex A. Adjei, Array BioPharma Inc (C); Roger B. Cohen, Array BioPharma Inc (C); Gilad Gordon, Array BioPharma Inc (C); S. Gail Eckhardt, AstraZeneca (C), Array BioPharma Inc (C) Stock Ownership: Clive Morris, AstraZeneca; David Wilson, AstraZeneca; Lara Maloney, Array BioPharma Inc; Kevin Litwiler, Array BioPharma Inc; Gregory Poch, Array BioPharma Inc Honoraria: None Research Funding: Roger B. Cohen, Array BioPharma Inc, AstraZeneca; S. Gail Eckhardt, AstraZeneca Expert Testimony: None Other Remuneration: S. Gail Eckhardt, AstraZeneca, fellowship funding

Figures

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 (

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.