A phase I, dose escalation trial of ZD0473, a novel platinum analogue, in combination with gemcitabine.
OBJECTIVE
To develop a combination regimen for clinical testing, we performed a dose escalation study of ZD0473 in combination with gemcitabine. ZD0473 is a novel platinum analogue with an aliphatic cyclic carrier ligand. In vitro and in vivo studies suggest that it possesses a different spectrum of antitumor activity from cisplatin and carboplatin. In single-agent studies of ZD0473, myelosuppression was the predominant toxicity and responses wer observed.


METHODS
In this combination phase I trial, 36 patients with advanced cancer were accrued to four dose levels, with doses of ZD0473 and gemcitabine ranging from 60 to 120 mg/m2 and 600 to 750 mg/m2, respectively ZD0473 was administered on day 1 and gemcitabine was given on days 1 and 8 of a 21-day cycle.


RESULTS
Hematologic toxicity was dose-limiting. Grade 3 and 4 thrombocytopenia and neutropenia occurred during 60% and 41% of all cycles. Nonhematologic toxicities were mild and reversible. Two partial responses and 19 patients with stable disease were observed.


CONCLUSIONS
The recommended phase II doses are 90 mg/m2 of ZD0473 and 750 mg/m2 of gemcitabine for lightly pretreated patients and 600 mg/m2 for heavily pretreated patients. The combination of ZD0473 and gemcitabine is associated with dose-dependent thrombocytopenia and neutropenia as well as having promising clinical activity.
Flaherty
Keith T
KT
Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA 19104, USA. ktflaherty@aol.com
Stevenson
James P
JP
Redlinger
Maryann
M
Algazy
Kenneth M
KM
Giatonio
Bruce
B
O'Dwyer
Peter J
PJ
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D000093542:Gemcitabine
D009944:Organoplatinum Compounds; C110525:amminedichloro(2-methylpyridine)platinum(II); D003841:Deoxycytidine; D000093542:Gemcitabine