Open-label, non-randomised, inter-individual dose escalation of ZK 304709 with the evaluation of safety, tolerability, pharmacokinetics, oral bioavailability and orientating efficacy after daily administration in patients with advanced cancer (7 d treatment and 14 d recovery).
OBJECTIVE
The primary objectives of this study were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of ZK 304709, a novel multi-targeted growth inhibitor (MTGI(trade mark)), in man. Secondary end-points included safety evaluation, tolerability, pharmacokinetic profiling and assessment of response using standard and novel surrogate pharmacodynamic end-points.


METHODS
Patients (n=40) with advanced solid malignancies were treated with ZK 304709, administered orally once daily for 7 d with 14 d recovery. Doses were escalated in sequential cohorts of three patients with expansion to 6-7 patients should a dose-limiting toxicity occur.


RESULTS
ZK 304709 was safely administered up to 360mg. However, above 90mg blood concentrations increased only slightly. As this dose was not deemed likely to result in meaningful pharmacologic or clinical activity, the trial was stopped before the MTD was ascertained. It was therefore not possible to make a reliable assessment of efficacy or pharmacodynamic end-points.


CONCLUSIONS
Due to the lack of further increment in blood concentrations above a dose of 90mg, which was felt from previous animal studies to be unlikely to result in meaningful pharmacologic or clinical activity, this study was stopped early.
Graham
Janet S
JS
Cancer Research UK, Department of Medical Oncology, University of Glasgow, Glasgow G61 1BD, UK. j.graham@imperial.ac.uk
Plummer
Ruth
R
McCoy
Candice
C
Kowal
Kristin
K
Wiesinger
Herbert
H
Detjen
Katharina
K
Calvert
Hilary
H
Wiedenmann
Bertram
B
Cassidy
Jim
J
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity*; D001682:Biological Availability; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D018579:Patient Selection; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors