Phase I trial of pazopanib in patients with advanced cancer.
OBJECTIVE
The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors.


METHODS
Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks.


RESULTS
Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of >or=800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C(24)) >or=15 microg/mL (34 micromol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of >or=6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of >or=800 mg once daily or 300 mg twice daily.


CONCLUSIONS
Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.
Hurwitz
Herbert I
HI
Duke University Medical Center, Durham, North Carolina, USA.
Dowlati
Afshin
A
Saini
Shermini
S
Savage
Shawna
S
Suttle
A Benjamin
AB
Gibson
Diana M
DM
Hodge
Jeffrey P
JP
Merkle
Elmar M
EM
Pandite
Lini
L
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000855:Anorexia / Q000139:chemically induced; D015331:Cohort Studies; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014839:Vomiting / Q000139:chemically induced
D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib