Phase I trial of the antifolate ZD9331 in combination with cisplatin in patients with refractory solid malignancies.
OBJECTIVE
To determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of ZD9331 in combination with cisplatin in patients with refractory solid tumors and to describe any preliminary antitumor activity associated with this regimen.


METHODS
Patients received combination therapy with ZD9331 as a 30-min infusion on days 1 and 8 of a 21-day cycle at doses of 100 or 130 mg/m(2), followed by cisplatin at 50 or 75 mg/m(2) as a 30- to 60-min infusion on day 1 only.


RESULTS
A total of 16 patients received 59 cycles of ZD9331 and cisplatin. Patients were enrolled at three dose levels: ZD9331/cisplatin 100/50 ( n=3), 130/50 ( n=9), 130/75 ( n=4). DLTs at 130/75 included thrombocytopenia, neutropenia, fatigue, nausea, vomiting and stomatitis. Among 15 evaluable patients, 2 showed a partial response (patients with mesothelioma and head and neck cancer) and 6 showed stable disease (for a median of 5.5 cycles).


CONCLUSIONS
ZD9331 in combination with cisplatin was well tolerated at a dose of 130/50 mg/m(2) after establishing the principal DLTs of neutropenia and thrombocytopenia. The combination shows evidence of antitumor activity in a pretreated population.
Bilenker
Joshua H
JH
Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
Stevenson
James P
JP
Flaherty
Keith T
KT
Algazy
Kenneth
K
McLaughlin
Kathy
K
Haller
Daniel G
DG
Giantonio
Bruce J
BJ
Koehler
M
M
Garcia-Vargas
J E
JE
O'Dwyer
Peter J
PJ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects
D005493:Folic Acid Antagonists; D011799:Quinazolines; C094299:ZD 9331; D002945:Cisplatin