An open-label, phase I study of the polo-like kinase-1 inhibitor, BI 2536, in patients with advanced solid tumors.
OBJECTIVE
This phase I, open-label, dose-escalation study investigated the maximum tolerated dose (MTD) of BI 2536, a small-molecule polo-like kinase (Plk)-1 inhibitor, in two treatment schedules in patients with advanced solid tumors. Secondary objectives included evaluation of safety, efficacy, and pharmacokinetics.


METHODS
Patients received a single i.v. dose of BI 2536 as a 1-hour infusion on days 1 and 8 or a single 24-hour infusion on day 1 of each 21-day treatment course. MTD determination was based on dose-limiting toxicities.


RESULTS
Forty-four and 26 patients received each treatment schedule, respectively. The MTD of BI 2536 in the day 1 and 8 schedule was 100 mg per administration (200 mg per course). The MTD for the second dosing schedule was not determined; a 225-mg dose was well tolerated. The most frequently reported treatment-related nonhematologic adverse events were gastrointestinal events and fatigue. Hematotoxicity as the most relevant side effect was similar in both schedules; neutropenia grades 3 and 4 were observed in 16 patients (36.4%) of the day 1 and 8 schedule and 13 patients (50%) of the 24-hour infusion. Fourteen patients (32%) treated in the day 1 and 8 dosing schedule had a best overall response of stable disease. Plasma concentrations of BI 2536 increased dose proportionally, with no relevant accumulation of exposure in the day 1 and 8 dosing schedule. The average terminal half-life was 50 hours.


CONCLUSIONS
BI 2536 administered in either treatment schedule has adequate safety in patients with advanced solid tumors, warranting further clinical investigation of polo-like kinase-1 inhibitors.
Hofheinz
Ralf-Dieter
RD
Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany.
Al-Batran
Salah-Eddin
SE
Hochhaus
Andreas
A
Jäger
Elke
E
Reichardt
Volker L
VL
Fritsch
Holger
H
Trommeshauser
Dirk
D
Munzert
Gerd
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D000097869:Polo-Like Kinase 1
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536