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.

• Authors: 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, S Gail Eckhardt
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 26 Issue 13 Pg. 2139-46 (May 01 2008) ISSN: 1527-7755 [Electronic] United States
• PMID: 18390968 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• AZD 6244
• Antineoplastic Agents
• Benzimidazoles
• KRAS protein, human
• Ki-67 Antigen
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• MAP2K2 protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Benzimidazoles (administration & dosage, adverse effects, pharmacokinetics)
• Cell Proliferation (drug effects)
• DNA Mutational Analysis
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Ki-67 Antigen (analysis)
• Leukocytes, Mononuclear (drug effects, enzymology)
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, metabolism)
• Male
• Maximum Tolerated Dose
• Melanoma (drug therapy, enzymology, genetics, pathology)
• Middle Aged
• Mutation
• Neoplasm Staging
• Neoplasms (drug therapy, enzymology, genetics, pathology)
• Phosphorylation
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins p21(ras)
• Treatment Outcome
• ras Proteins (genetics)