Sg. Eckhardt et al., Phase I and pharmacologic study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors, J CL ONCOL, 17(4), 1999, pp. 1095-1104
Purpose: 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.
Patients and Methods: Twenty-six patients were treated with SU101 doses ran
ging from 15 to 443 mg/m(2) as a 24-hour continuous intravenous (IV) infusi
on weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were
performed to characterize the disposition of SU101 and its major active me
tabolite, SU0020. Immunohistochemical staining of PDGF-alpha and -beta rece
ptors was performed on malignant tumor specimens obtained at diagnosis.
Results: Twenty-six patients were treated with 52 courses (187 infusions) o
f SU101. The most common toxicities were mild to moderate nausea, vomiting,
and fever. two patients experienced one episode each of grade 3 neutropeni
a at the 333 and 443 mg/m(2) dose levels. Dose escalation of SU101 above 44
3 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 e
limination of SU0020. SU101 was rapidly converted to SU0020, which exhibite
d 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 ra
nged from 54 to 522 mu mol/L. Immunohistochemical studies revealed PDGF-alp
ha and -beta receptor staining in the majority (15 of 19) of malignant neop
lasms.
Conclusion: 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. Altho
ugh further dose escalation was precluded by infusate volume constraints, t
his SU101 dose schedule resulted in the achievement and maintenance of subs
tantial plasma concentrations of the major metabolite, SU0020, for the enti
re treatment period. (C) 1999 by American Society of Clinical Oncology.