A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors.
OBJECTIVE
HMN-214 is an oral prodrug of HMN-176, a stilbene derivative that interferes with the subcellular spatial location of polo-like kinase-1, a serine/threonine kinase that regulates critical mitotic events. We conducted a dose escalation study of HMN-214 in patients with advanced cancer to assess the safety profile and pharmacokinetics of HMN-214 and to establish the maximum tolerated dose.


METHODS
Thirty-three patients were enrolled onto four dosing cohorts of HMN-214 from 3 to 9.9 mg/m2/d using a continuous 21-day dosing schedule every 28 days, with pharmacokinetic sampling during cycle 1.


RESULTS
A severe myalgia/bone pain syndrome and hyperglycemia were dose-limiting toxicities at 9.9 mg/m2/d. A dose reduction and separate enrollment by pretreatment status (lightly versus heavily pretreated) was undertaken, with one dose-limiting toxicity (grade 3 bone pain) at 8 mg/m2/d. The maximum tolerated dose was defined as 8 mg/m2/d for both treatment cohorts. Dose-proportional increases were observed in AUC but not Cmax. There was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease as best tumor response, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient decline in carcinoembryonic antigen in a patient with colorectal cancer was noted.


CONCLUSIONS
The maximum tolerated dose and recommended phase II dose of HMN-214 when administered on this schedule was 8 mg/m2/d regardless of pretreatment status. Further development of HMN-214 will focus on patient populations for which high expression of polo-like kinase-1 is seen (i.e., prostate and pancreatic cancer patients).
Garland
Linda L
LL
Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA. lgarland@azcc.arizona.edu
Taylor
Charles
C
Pilkington
Deborah L
DL
Cohen
Jan L
JL
Von Hoff
Daniel D
DD
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001597:Benzylidene Compounds / Q000097:blood / Q000652:urine; D018797:Cell Cycle Proteins / Q000187:drug effects*; D015331:Cohort Studies; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013267:Stilbenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D000097869:Polo-Like Kinase 1
D001597:Benzylidene Compounds; D018797:Cell Cycle Proteins; D003497:Cyclic N-Oxides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D013267:Stilbenes; D013449:Sulfonamides; D000097869:Polo-Like Kinase 1; C479799:(E)-4-((2-N-(4-methoxybenzenesulfonyl)amino)stilbazole)1-oxide; C487781:(E)-4-(2-(2-(N-acetyl-N-(4-methoxybenzenesulfonyl)amino)stilbazole)) 1-oxide