JCO Early Release, published online ahead of print Apr 7 2008
Journal of Clinical Oncology, 10.1200/JCO.2007.14.4956
Received October 16, 2007
Accepted December 21, 2007
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
Alex A. Adjei,* Roger B. Cohen, Wilbur Franklin, Clive Morris, David Wilson, Julian R. Molina, Lorelei J. Hanson, Lia Gore, Laura Chow, Stephen Leong, Lara Maloney, Gilad Gordon, Heidi Simmons, Allison Marlow, Kevin Litwiler, Suzy Brown, Gregory Poch, Katie Kane, Jerry Haney, and S. Gail Eckhardt
From the Mayo Clinic, Rochester, MN; Fox Chase Cancer Center, Philadelphia, PA; University of Colorado Health Sciences Center, Denver; Array BioPharma Inc, Boulder, CO; and AstraZeneca, Alderley Park, United Kingdom.
* To whom correspondence should be addressed. E-mail: alex.adjei{at}roswellpark.org
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  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 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.
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