TY - JOUR
T1 - Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors
AU - Ricart, Alejandro D.
AU - Berlin, Jordan D.
AU - Papadopoulos, Kyriakos P.
AU - Syed, Samira
AU - Drolet, Daniel W.
AU - Quaratino-Baker, Charlotte
AU - Horan, Julie
AU - Chick, Jon
AU - Vermeulen, Wendy
AU - Tolcher, Anthony W.
AU - Rowinsky, Eric K.
AU - Rothenberg, Mace L.
PY - 2008/12/1
Y1 - 2008/12/1
N2 - Purpose:To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors. Experimental Design:CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored:60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m 2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated. Results:Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m 2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m 2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m 2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity. Conclusions:The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m 2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.
AB - Purpose:To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors. Experimental Design:CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored:60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m 2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated. Results:Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m 2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m 2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m 2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity. Conclusions:The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m 2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.
UR - http://www.scopus.com/inward/record.url?scp=59449093705&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=59449093705&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-08-0864
DO - 10.1158/1078-0432.CCR-08-0864
M3 - Article
C2 - 19047127
AN - SCOPUS:59449093705
SN - 1078-0432
VL - 14
SP - 7947
EP - 7955
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -