Phase I and pharmacologic study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors.
OBJECTIVE
To evaluate the clinical feasibility and pharmacologic behavior of the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor SU101, administered on a prolonged, intermittent dosing schedule to patients with advanced solid malignancies.


METHODS
Twenty-six patients were treated with SU101 doses ranging from 15 to 443 mg/m(2) as a 24-hour continuous intravenous (IV) infusion weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were performed to characterize the disposition of SU101 and its major active metabolite, SU0020. Immunohistochemical staining of PDGF-alpha and -beta receptors was performed on malignant tumor specimens obtained at diagnosis.


RESULTS
Twenty-six patients were treated with 52 courses (187 infusions) of SU101. The most common toxicities were mild to moderate nausea, vomiting, and fever. Two patients experienced one episode each of grade 3 neutropenia at the 333 and 443 mg/m(2) dose levels. Dose escalation of SU101 above 443 mg/m(2)/wk was precluded by the total volume of infusate required, 2.5 to 3.0 L. Individual plasma SU101 and SU0020 concentrations were described by a one-compartment model that incorporates both first-order formation and elimination of SU0020. SU101 was rapidly converted to SU0020, which exhibited a long elimination half-life averaging 19 +/- 12 days. At the 443 mg/m(2)/wk dose level, trough plasma SU0020 concentrations during weeks 2 and 4 ranged from 54 to 522 micromol/L. Immunohistochemical studies revealed PDGF-alpha and -beta receptor staining in the majority (15 of 19) of malignant neoplasms.


CONCLUSIONS
SU101 was well tolerated as a 24-hour continuous IV infusion at doses of up to 443 mg/m(2)/wk for 4 consecutive weeks every 6 weeks. Although further dose escalation was precluded by infusate volume constraints, this SU101 dose schedule resulted in the achievement and maintenance of substantial plasma concentrations of the major metabolite, SU0020, for the entire treatment period.
Eckhardt
S G
SG
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. geckhardt@saci.org
Rizzo
J
J
Sweeney
K R
KR
Cropp
G
G
Baker
S D
SD
Kraynak
M A
MA
Kuhn
J G
JG
Villalona-Calero
M A
MA
Hammond
L
L
Weiss
G
G
Thurman
A
A
Smith
L
L
Drengler
R
R
Eckardt
J R
JR
Moczygemba
J
J
Hannah
A L
AL
Von Hoff
D D
DD
Rowinsky
E K
EK
D000328:Adult; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007555:Isoxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000077339:Leflunomide; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D006131:Growth Inhibitors; D007555:Isoxazoles; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D000077339:Leflunomide