A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI), in patients with advanced solid tumours.
OBJECTIVE
The toxicities, pharmacokinetics and recommended dose of oral once daily ZK 304709, a novel multi-targeted growth inhibitor (MTGI) with activity against cell-cycle progression and angiogenesis, was investigated in patients by administration for 14 consecutive days followed by 14 days recovery.


METHODS
Patients with solid tumours resistant to standard treatments were enrolled in an accelerated titration design.


RESULTS
Thirty-seven patients received ZK 304709 from 15 to 285 mg daily. The most common drug-related adverse events were vomiting, diarrhoea and fatigue. Systemic exposure to ZK 304709 increased with dose up to 90 mg daily but plateaued thereafter, with high inter-individual variability at all doses. Thirteen patients had stable disease as best response as per RECIST criteria.


CONCLUSIONS
There was no increase in exposure to ZK 304709 with dose escalation above 90 mg, and the MTD was not determined. This study illustrates the importance of phase I pharmacokinetic data to guide dose escalation and drug development.
Scott
Edwina N
EN
Department of Oncology, University of Leicester, Leicester Royal Infirmary, Leicester, LE1 5WW, England, UK.
Thomas
Anne L
AL
Molife
L Rhoda
LR
Ahmed
Samreen
S
Blagden
Sarah
S
Fong
Peter C
PC
Kowal
Kristin
K
McCoy
Candice
C
Wiesinger
Herbert
H
Steward
Will
W
De Bono
Johann
J
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006131:Growth Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D012449:Safety; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006131:Growth Inhibitors