Phase I, Pharmacokinetic and Biological Correlative Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor, and Cisplatin in Patients with Solid Tumors

• Published in: Clinical cancer research Vol. 14; no. 23; pp. 7947 - 7955
• Main Authors: RICART, Alejandro D, BERLIN, Jordan D, ROWINSKY, Eric K, ROTHENBERG, Mace L, PAPADOPOULOS, Kyriakos P, SYED, Samira, DROLET, Daniel W, QUARATINO-BAKER, Charlotte, HORAN, Julie, CHICK, Jon, VERMEULEN, Wendy, TOLCHER, Anthony W
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-12-2008
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biological and medical sciences; Cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; Female; Genotype; Glutarates - administration & dosage; Glutarates - adverse effects; Glutarates - pharmacokinetics; Homocysteine - blood; Humans; Isoindoles - administration & dosage; Isoindoles - adverse effects; Isoindoles - pharmacokinetics; Liposome; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; OSI-7904L; Pharmacokinetic; Pharmacology. Drug treatments; Phase I; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Quinazolines - administration & dosage; Quinazolines - adverse effects; Quinazolines - pharmacokinetics; Thymidylate Synthase - genetics; Tumors; Antineoplastic agent; Human; Solid tumor; Enzyme; Transferases; Liposome; Patient; Malignant tumor; Thymidylate synthase; Cisplatin; Alkylating agent; Methyltransferases; Inhibitor; Pharmacokinetics; Cancer; Platinum II Complexes
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0864

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.