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.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Adjei
Alex A
AA
Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. alex.adjei@roswellpark.org
Cohen
Roger B
RB
Franklin
Wilbur
W
Morris
Clive
C
Wilson
David
D
Molina
Julian R
JR
Hanson
Lorelei J
LJ
Gore
Lia
L
Chow
Laura
L
Leong
Stephen
S
Maloney
Lara
L
Gordon
Gilad
G
Simmons
Heidi
H
Marlow
Allison
A
Litwiler
Kevin
K
Brown
Suzy
S
Poch
Gregory
G
Kane
Katie
K
Haney
Jerry
J
Eckhardt
S Gail
SG
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C117307:KRAS protein, human; D019394:Ki-67 Antigen; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins