Study of a NewNucleosideAnalogue , OSI-7836 , Using TwoAdministration Schedules in Patientswith Advanced SolidMalignancies

Purpose:To investigate the safety, tolerability, and pharmacokinetic profile of the novel nucleoside analogue OSI-7836 in patients with advanced solid malignancies. Experimental Design: OSI-7836 was initially given as a 60-minute i.v. infusion on day 1every 21days. In viewof its dose-limiting toxicities, the administration timewas amended to a 5-minute bolus, and subsequently, the schedulewas amended toweekly for 4weeks followedby a 2-week rest. Blood and urine samples were collected for pharmacokinetic studies. Analyses of cytokines and lymphocyte subsets were added later in the study to elucidate a mechanism for the severe fatigue and lymphocyte depletion observed in earlier patients. Results:Thirty patients receiveda totalof 61treatment cycles. Fatiguewas themaindose-limiting toxicity. Maximum-tolerated dose was defined as 300 mg/m in the 60-minute infusion, (three times per week) schedule; 400 mg/m in the 5-minute bolus infusion, (three times per week) schedule; and 100 mg/m in the weekly schedule. Other common toxicities were nausea, vomiting, rash, fever, and a flu-like syndrome. There were no clinically significant hematologic toxicities. Following the initial dose, OSI-7836was eliminated fromplasmawith amedian (range) elimination half-life of 48.3 minutes (22.6-64.8 minutes). Lymphocyte subset analysis showed a significant drop in B cell counts, which persisted to day 14 and beyond. Cytokine analysis showed significant elevations of interleukin-6 and interleukin-10 in all patients who received z200mg/m OSI-7836. Best response was disease stabilization in seven patients. Conclusion: OSI-7836 was associated with excessive fatigue, and despite changes in its schedule and duration of administration, we did not observe an improvement in its tolerability. Its potentially selective effect on B lymphocytes could be exploited in further studies in specific hematologic malignancies. The nucleoside analogues are an important class of chemotherapeutic drugs, which include cytarabine [1-h-D-arabinofuranosylcytosine (ara-C)], fludarabine, cladribine, and gemcitabine. They act by competing with natural nucleosides for incorporation into newly synthesized DNA or RNA. Gemcitabine is the only nucleoside analogue with antitumor activity against solid tumors. It has been shown to have pharmacologic properties distinct to the other nucleoside analogues, which explains its broader range of activity as well as schedule dependency. Following conversion to its triphosphate, gemcitabine seems to be retained in tumor cells for a longer period of time than the other nucleoside analogues (1, 2). Furthermore, compared with ara-C, the intracellular levels of gemcitabine triphosphate was found to be 20-fold greater than those seen with ara-C 5V-triphosphate at equimolar concentrations of the parent compounds (3). Xenograft studies using prolonged infusions of gemcitabine showed superior activity compared with bolus injections (4). Phase I studies of gemcitabine have shown that the ability of cells to accumulate gemcitabine triphosphate was saturable (5–7), suggesting that a prolonged infusion might lead to greater intracellular drug exposure, the optimal dose rate being found to be 10 mg/m/ min. Recently a randomized phase II trial of gemcitabine in patients with pancreatic cancer comparing a standard 30minute infusion with a fixed dose rate of 10 mg/m/min showed superior overall survival using the fixed dose rate infusion (8). Gemcitabine has also been shown to be schedule dependent (9). Clinically, gemcitabine has been investigated in a variety of schedules (10, 11). Frequent administration (e.g., daily or twice-a-week schedules) was found to be more toxic than less frequent schedules given weekly. However, less frequent administration was associated with lower efficacy. Cancer Therapy: Clinical Authors’ Affiliations: Royal Marsden Hospital, Sutton, United Kingdom; Erasmus University Medical Centre, Rotterdam, the Netherlands ; OSI Pharmaceuticals, Inc., Oxford, United Kingdom; OSI Pharmaceuticals, Inc., Melville, NewYork; and OSIPharmaceuticals, Inc., Boulder, Colorado Received 9/2/05; revised 2/4/06; accepted 2/21/06. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Chooi P. Lee, Andrew Love Cancer Centre, Barwon Health, Swanston Street, Geelong,Victoria 3220, Australia. Phone: 61-3-52267851; Fax: 61-3-5260-3157; E-mail: chooil@barwonhealth.org.au. F2006 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-1932 www.aacrjournals.org Clin Cancer Res 2006;12(9) May1, 2006 2841 Research. on May 4, 2017. © 2006 American Association for Cancer clincancerres.aacrjournals.org Downloaded from OSI-7836, 4V-thio-ara-C, is a new member of the class of nucleoside analogues (12, 13). As with other nucleoside analogues, OSI-7836 is a prodrug and requires intracellular phosphorylation by deoxycytidine kinase to the active form (OSI-7836-triphosphate), which then competes with deoxycytidine for incorporation into DNA resulting in cell death. Although OSI-7836 is similar to ara-C as a substrate for phosphorylation by deoxycytidine kinase, it seems to be a weaker substrate than gemcitabine, potentially explaining the higher IC50 for OSI-7836 relative to gemcitabine observed in in vitro experiments (12). Similarly, the metabolism of OSI7836 is via deamination, resulting in the formation of 4V-thio-hD-arabinofuranosyluracil (4V-thio-ara-U), which is inactive in terms of antitumor activity. However, several differences in biochemical metabolism were observed between OSI-7836 and other nucleoside analogues: in CEM T-cell leukemia cells, OSI7836 triphosphate (OSI-7836-TP) accumulated more slowly with 100-fold less incorporation into DNA compared with araC 5V-triphosphate. OSI-7836, however, was found to be less susceptible to metabolic clearance by deamination via deoxycytidine and dCMP deaminase compared with gemcitabine and ara-C, resulting in greater cellular retention and a longer halflife (six times that of gemcitabine). This could explain the relatively higher antitumor activity of OSI-7836 in solid tumor xenografts (12). In xenograft studies using lung, colon, pancreatic, breast, and melanoma models, OSI-7836 has shown superior antitumor activity in most of these tumors, particularly in lung and pancreatic models, compared with gemcitabine, cisplatin, and paclitaxel. OSI-7836 was shown to be less schedule dependent than gemcitabine, showing antitumor activity with a variety of schedules that included day 1, days 1 and 8, and days 1, 4, 7, and 10 scheduling (13, 14). Furthermore, giving OSI-7836 over a longer infusion duration did not improve its antitumor activity, in contrast to gemcitabine (4). In dogs, 930 mg/m was found to be the maximum tolerated dose based on gastrointestinal toxicity, fever, and myelotoxicity. Repeated dose studies with day 1, days 1 and 8, and days 1, 2, and 3 schedules were done at 60, 240, 500, and 1,000 mg/m in dogs. All doses were well tolerated with no cumulative toxicities seen after two cycles. Pharmacokinetic studies in dogs and mice showed approximate dose linear relationships across the ranges tested, with similar plasma clearance rates between dogs and CD-1 mice. In mice, f68% of the dose was recovered in urine as unchanged drug or as the deaminated metabolite 4Vthio-ara-U. Phase I evaluation of OSI-7836 given as a 30-minute infusion on days 1 and 8 every 3 weeks had already commenced in Canada under the auspices of National Cancer Institute of Canada (15). We did this phase I study of OSI-7836 to investigate an alternative schedule of administration, as a 1-hour infusion on day 1 every 3 weeks. Materials and Methods Patient eligibility. Inclusion criteria for the study were histologically or cytologically proven advanced and/or metastatic solid malignancy or lymphoproliferative disease refractory to standard therapy or for which no effective therapy was available; age z 18 years; Eastern Cooperative Oncology Group performance status V 2; life expectancy z 3 months; >4 weeks since previous treatment with chemotherapy (6 weeks for mitomycin C and nitrosureas) or >3 weeks since previous radiotherapy (unless a low-dose treatment was given); patients must have recovered from any treatment-related toxicities before study entry; recovery from any previous surgery; adequate hematologic, renal, and hepatic function (neutrophil count z 1.5 10 /L, platelet count z 100 10/L; serum creatinine V 1.5 upper limit of normal range; bilirubin V 1.5 upper limit of normal; aspartate aminotransferase and/or alanine aminotransferase V 2.5 upper limit of normal, or V5 upper limit of normal if patient had liver metastases); and women of child-bearing potential must have had a negative pregnancy test and agreed to using contraceptive measures throughout study. Exclusion criteria were concurrent anticancer therapy; pregnant or lactating women; unstable, symptomatic brain metastasis; and patients with uncontrolled infections or with serious concurrent medical