Phase I and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies.
OBJECTIVE
To assess the feasibility of administering troxacitabine, an L-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity.


METHODS
Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m(2)) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin.


RESULTS
Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m(2), respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196-396 L and 7.2-9.8 L/h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42% reduction in extent of disease for 6 months.


CONCLUSIONS
The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75/6.4 and 50/4.8 mg/m(2), every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine.
Lin
Chia-Chi
CC
The Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA.
Beeram
Muralidhar
M
Rowinsky
Eric K
EK
Takimoto
Chris H
CH
Ng
Chee M
CM
Geyer
Charles E
CE
Denis
Louis J
LJ
De Bono
Johann S
JS
Hao
Desiree
D
Tolcher
Anthony W
AW
Rha
Sun-Young
SY
Jolivet
Jacques
J
Patnaik
Amita
A
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004148:Dioxolanes / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced*; D013921:Thrombocytopenia / Q000139:chemically induced*; D014018:Tissue Distribution; D016896:Treatment Outcome; D055815:Young Adult
D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine; D002945:Cisplatin