Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.
OBJECTIVE
To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416.


METHODS
Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine.


RESULTS
In the first cohort of three patients entered at the 85 mg/m(2) dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m(2)), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m(2) developed a thromboembolic event. The dose was then reduced to 85 mg/m(2) in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle-dependent manner.


CONCLUSIONS
The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.
Kuenen
Bart C
BC
Departments of Medical Oncology and Pulmonology, Vrije Universiteit Medical Center.
Rosen
Lee
L
Smit
Egbert F
EF
Parson
Mandy R N
MR
Levi
Marcel
M
Ruijter
Rita
R
Huisman
Holger
H
Kedde
Marc A
MA
Noordhuis
Paul
P
van der Vijgh
Wim J F
WJ
Peters
Godefridus J
GJ
Cropp
Gillian F
GF
Scigalla
Paul
P
Hoekman
Klaus
K
Pinedo
Herbert M
HM
Giaccone
Giuseppe
G
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics; D013923:Thromboembolism / Q000139:chemically induced; D016896:Treatment Outcome; D000093542:Gemcitabine
D007211:Indoles; D011758:Pyrroles; D003841:Deoxycytidine; C116890:Semaxinib; D002945:Cisplatin; D000093542:Gemcitabine