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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Royal Marsden Hospital, Sutton, United Kingdom; 2 Erasmus University Medical Centre, Rotterdam, the Netherlands; 3 OSI Pharmaceuticals, Inc., Oxford, United Kingdom; 4 OSI Pharmaceuticals, Inc., Melville, New York; and 5 OSI Pharmaceuticals, Inc., Boulder, Colorado
Requests for reprints: Chooi P. Lee, Andrew Love Cancer Centre, Barwon Health, Swanston Street, Geelong, Victoria 3220, Australia. Phone: 61-3-5226-7851; Fax: 61-3-5260-3157; E-mail: chooil{at}barwonhealth.org.au.
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Abstract |
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Experimental Design: OSI-7836 was initially given as a 60-minute i.v. infusion on day 1 every 21 days. In view of its dose-limiting toxicities, the administration time was amended to a 5-minute bolus, and subsequently, the schedule was amended to weekly for 4 weeks followed by 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 received a total of 61 treatment cycles. Fatigue was the main dose-limiting toxicity. Maximum-tolerated dose was defined as 300 mg/m2 in the 60-minute infusion, (three times per week) schedule; 400 mg/m2 in the 5-minute bolus infusion, (three times per week) schedule; and 100 mg/m2 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-7836 was eliminated from plasma with a median (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 
200 mg/m2 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.
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 5'-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/m2/min. Recently a randomized phase II trial of gemcitabine in patients with pancreatic cancer comparing a standard 30-minute infusion with a fixed dose rate of 10 mg/m2/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.
OSI-7836, 4'-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 OSI-7836 is via deamination, resulting in the formation of 4'-thio-ß-D-arabinofuranosyluracil (4'-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, OSI-7836 triphosphate (OSI-7836-TP) accumulated more slowly with 100-fold less incorporation into DNA compared with ara-C 5'-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 half-life (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/m2 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/m2 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, 
68% of the dose was recovered in urine as unchanged drug or as the deaminated metabolite 4'-thio-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.
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18 years; Eastern Cooperative Oncology Group performance status 
2; life expectancy 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 1.5 x 109 /L, platelet count 100 x 109/L; serum creatinine 1.5x upper limit of normal range; bilirubin 1.5x upper limit of normal; aspartate aminotransferase and/or alanine aminotransferase 2.5x upper limit of normal, or 5x 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 conditions.
Study design. This was a phase I, open-label, dose escalation study of OSI-7836 conducted at two centers: The Royal Marsden Hospital, Sutton, United Kingdom and Erasmus University Medical Centre, Rotterdam, the Netherlands. The study protocol was approved by the Ethics Committee of both centers. All patients gave written, informed consent before study entry and were registered with OSI Pharmaceuticals, Inc.
Pretreatment investigations. All patients had the following pretreatment assessments: history and physical examination that included documentation of residual toxicity from previous therapy, full blood count, biochemistry, urinalysis, and electrocardiogram. Women of child-bearing potential had a pregnancy test. Baseline tumor imaging using X-rays, computed tomography, or magnetic resonance imaging scan was also done.
Treatment administration and dose escalation. OSI-7836 was supplied by OSI Pharmaceuticals (Oxford, United Kingdom) in 500-mg vials as a white to tan cake or powder. Drug in each vial was reconstituted in 4.6 mL water and diluted in 0.9% sodium chloride as required to the appropriate concentration. A 5-HT3 antagonist and dexamethasone were given as premedications according to local institutional guidelines, based on data from the Canadian Phase I study of OSI-7836 (15), which suggested these prophylactic antiemetics were required at OSI-7836 doses of 200 mg/m2.
OSI-7836 was initially planned to be given as a 60-minute i.v. infusion on day 1 every 21 days. A starting dose of 200 mg/m2 was chosen based on the highest safe dose of OSI-7836 previously given in a concurrent phase I study of OSI-7836 in Canada (15). In view of toxicities seen with this 60-minute infusion, the protocol was amended to administer OSI-7836 as a 5-minute i.v. bolus on the same schedule to investigate the possibility that shorter infusions could ameliorate some of these dose-limiting toxicities (DLT). This was based on mouse models (in which 6- and 24-hour infusions were tested) as well as preliminary evidence from the Canadian Phase I study (15) that longer infusions were more toxic. A second protocol amendment was made to investigate administering drug as a 5-minute bolus injection weekly for 4 weeks followed by a 2-week rest, with a starting dose of 100 mg/m2, to investigate whether the dose intensity could be maintained without encountering excessive nonhematologic toxicities seen previously at the higher dose level of 200 mg/m2.
Dose escalation was based on the safety assessment of the previous treatment cohort. If toxicity was limited to grade 0 or 1, then escalations up to 100% were considered, whereas the occurrence of a grade 2 event would permit increases only from 30% to 50%; the occurrence of grade 3 toxicity would limit any increase to 20% to 29%. A minimum of three patients were enrolled per dose level. Once a DLT was observed in one of three patients, up to three additional patients were treated at that dose level. The maximum tolerated dose was defined as the dose at which at least two of six patients experienced a DLT. The recommended dose was then determined to be the highest safe dose below the maximum tolerated dose. Once the recommended dose had been identified, a total of up to 10 patients were to be treated to more accurately assess potential interpatient variability in safety and tolerability.
Toxicity assessment. Patients were reviewed every week for toxicity assessment. Full blood count and biochemistry were done weekly (twice weekly full blood count in cycle 1) and more frequently in the event of grade 3 toxicity. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0).
DLT. Any of the following events occurring during cycle 1 were considered a DLT: grade 4 neutropenia lasting 7 days, febrile neutropenia grade 3, grade 3 or 4 infection with grade 3 or 4 neutropenia, platelet count < 25 x 109/L or thrombocytopenic bleeding, any grade 3 or 4 nonhematologic toxicity (excluding inadequately treated nausea or vomiting), persistent grade 2 (7 days) neurologic, cardiac or any other end organ toxicity (excluding alopecia), and inability to administer the cycle 2 dose by day 35; in the weekly schedule, omission of dosing on days 8, 15, and/or 22 or inability to administer the cycle 2 day 1 dose on day 56.
Response assessment. Tumor measurements were done after every three cycles using the Response Evaluation Criteria in Solid Tumors criteria (16). For patients enrolled to receive treatment as a weekly schedule, tumor measurements were done after every two cycles. Patients who received at least one cycle of treatment were evaluable for response.
Pharmacokinetic studies. Plasma and urine samples were collected from patients following dosing on cycle 1, day 1. For patients receiving OSI-7836 as a weekly injection for 4 weeks, plasma samples were also collected following the day 22 dose.
Venous samples of 3 mL were collected into an EDTA vacutainer containing 30 µg tetrahydrouridine. Patients receiving a 60-minute infusion had blood collected at 0.5, 1, 1.08, 1.25, 1.5, 2, 3, 5, 7, and 25 hours from the start of infusion. Patients receiving a 5-minute infusion had blood collected at 5, 10, 20, and 35 minutes and at 2, 4, 6, and 24 hours from the start of infusion. Blood samples were centrifuged (at 1,500-2,000 x g for 10 minutes) within 30 minutes of collection to obtain plasma and stored at –20°C until analysis.
Urine samples were collected over the following time intervals: before infusion, 0 to 4, 4 to 7, and 7 to 24 hours after the start of infusion. A 10-mL aliquot of urine from each collection time interval was taken and frozen at –20°C or below until analysis.
Plasma and urine samples were evaluated for OSI-7836 and its deaminated metabolite 4'-thio-ara-U, using validated liquid chromatography tandem mass spectroscopy methods (Cedra Corp., Austin, TX; ref. 17). Plasma concentration-time data for OSI-7836 and 4'-thio-ara-U were analyzed by noncompartmental methods using WinNonlin version 4.1 (Pharsight Corp., Mountain View, CA).
Statistical analysis. For the pharmacokinetic assessment, a two-way ANOVA on log dose-normalized AUC was done to test for differences between genders and infusion length. For analyses of half-lives, a two-way ANOVA on the ranks of the half-lives were done to test for effects due to gender and infusion length.
Cytokine and lymphocyte subset analysis. Assessment of cytokines and lymphocyte subsets was added at the time of schedule modification in an attempt to elucidate a mechanism for the severe fatigue and lymphocyte depletion observed in earlier patients. For cytokines, blood samples were collected from each patient at the following time points: day 1 (pre-dose and 6 hours post-dose) and days 2, 4, 8, and 15. Additional samples were collected on days 22 and 43 for patients receiving the weekly schedule. Blood samples were processed to provide duplicate serum samples of 0.5 to 1.0 mL. Assessment of cytokines included IFN-
; interleukin-1 (IL-1), IL-2, IL-4, IL-5, IL-6, and/or IL-10; and tumor necrosis factor-
. Levels were determined using the BD Human Th1/Th2 Cytokine Cytometric Bead Array kit (Becton Dickinson, Franklin Lakes NJ). Analysis of lymphocyte subsets (B lymphocytes, natural killer cells, total T lymphocytes, helper T cells, and cytotoxic T cells) was done on blood samples collected from each patient at the following time points: day 1 (pre-dose and 6 hours post-dose) and days 2, 4, 8, and 15. Additional samples were collected on days 22, 29, 36, and 43 for patients receiving the weekly schedule. Changes over time were plotted as a percentage of the total lymphocyte count for each subset.
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2 grades at a median onset of 3.5 days (range, 2-46 days), with a slight trend for a greater increase at the higher dose or protracted OSI-7836 dosing, although the small number of patients treated precludes rigorous statistical analysis (Table 4). The symptom generally improved upon cessation of treatment.
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One patient (patient 14) with mesothelioma developed acute tumor pain and inflammation associated with dyspnea 1 day after receiving the first cycle of his treatment at 300 mg/m2 (5-minute bolus) every 3 weeks. He was found to have superior vena cava obstruction and was treated with dexamethasone and radiotherapy to his mediastinal disease starting on day 4. As the patient had regression of his tumor outside radiotherapy field, which was attributed to the administration of OSI-7836, he was given a second cycle of treatment, which was delayed by 6 weeks due to the above event, at a reduced dose of 200 mg/m2. On day 3, he experienced acute pain and inflammation of his chest wall tumor similar to his experience during cycle 1. This resolved within 8 days.
Although lymphopenia (see Lymphocyte Subset Analysis) was the only significant hematologic toxicity seen (data not shown), only a small number of patients developed herpes simplex reactivation. Grade 3 thrombocytopenia was observed in only one patient.
The only significant biochemical toxicity was a grade 3 increase in creatinine in one patient. However, there were other contributing factors and the event improved to grade 1 within 5 days.
Response. Twenty-seven patients who received at least one cycle of treatment were evaluable for response. There were no objective responses; however, seven patients achieved disease stabilization with a median duration of 3.7 months (range, 1.9-5.4 months). In four of these patients, treatment was stopped after a median of 2.5 cycles due to toxicity.
Pharmacokinetic analysis. Following the initial OSI-7836 dose, complete plasma pharmacokinetic data were obtained from 28 patients (Fig. 1 ; Table 5 ). For two additional patients, only half-life of elimination data were obtained.
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No significant gender effect (P = 0.73) or infusion length effect (P = 0.74) was observed for dose-normalized AUC0 
. Plasma AUC0 was approximately dose proportional, although there was a trend for increased plasma clearance in the 100 mg/m2 dose cohort (Fig. 2
; Table 5). Weighed (1/x2) linear regression of AUC0 versus dose resulted in a coefficient of determination (r2) of 0.65. A run test found no significant deviation from the linear model, although the 95% confidence interval for the y intercept did not include 0 (–3.31 to –0.39). The median (range) plasma clearance across all dose cohorts was 36.2 L/hr m2 (21.9-63.6 L/hr m2).
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of the inactive metabolite 4'-thio-ara-U was much greater than that of OSI-7836 and also increased approximately proportionally with dose (data not shown). Across all day 1 doses, the 4'-thio-ara-U AUC0 was 9.69 ± 2.97-fold (mean ± SD) greater than the OSI-7836 AUC0 . After the initial dose of OSI-7836, the median (range) terminal half-life of 4'-thio-ara-U was 5.30 hours (1.00-11.4 hours), and it is this 6.6-fold slower elimination half-life that accounts for the greater AUC for 4'-thio-ara-U. Adequate 24-hour urine data were obtained from 23 patients following the cycle 1, day 1 dose of OSI-7836. The median fraction of the total dose recovered in urine was 83.6%, with the majority recovered as 4'-thio-ara-U.
For patients who received 100 mg/m2 in the weekly schedule, complete pharmacokinetic data were obtained from three patients, whereas elimination half-life data were obtained from four patients following the cycle 1, day 22 dose (data not shown). The median half-life of elimination for this cohort on day 22 was 46.1 minutes (n = 4) compared with 44.8 minutes (n = 5) for the same dose cohort on day 1. The median (range) plasma AUC0 was 2.00 hr µg/mL (1.57-2.44 hr µg/mL) and 2.81 hr µg/mL (2.11-4.11 hr µg/mL) following the day 1 and 22 doses, respectively.
Lymphocyte subset analysis. Because total lymphocyte counts were decreased, both B- and T-cell numbers were normalized to total lymphocyte count for exploratory subset analyses. Missing baseline values from the fluorescence-activated cell sorter analysis in six patients necessitated the substitution of separate clinical laboratory values for total lymphocyte counts. Although technical difficulties and missing data points precluded a rigorous analysis, an interesting pattern of B-cell response to OSI-7836 emerged in virtually all patients. Following a brief initial spike (range, 6-72 hours) in most patients, B-cell counts decreased rapidly between days 3 and 5, with a median nadir of 40% of baseline values at day 7 that persisted to day 14 following a single dose of drug on day 1 (data not shown). B-cell counts from patients on the weekly dosing regimen showed a further decrease to <20% of baseline values that persisted for the duration of dosing. By contrast, T-cell subsets initially showed a shallow dip (median 80% of baseline), recovered, and remained consistently close to baseline for patients on both dosing regimens (data not shown). Because time points were not collected beyond 2 weeks for the q21 day schedule, no assessment of recovery could be made or compared with the weekly dosing regimen.
Cytokine analysis. Substantial elevations in IL-6 and IL-10 were observed in all patients receiving at least 200 mg/m2 OSI-7836. Peak concentrations occurred between 6 and 24 hours for IL-10 (data not shown) and at 24 hours for IL-6 after dosing (data not shown). These elevations that have been associated with down-regulation of the immune response occurred in general before and continued concomitantly with the overall depletion of lymphocytes seen in these patients. Of the five patients treated in the weekly regimen, only one patient (patient 29) exhibited this same prolonged elevation of IL-10, and this patient also exhibited a more rapid initial decline in B lymphocytes. This same patient was also the only one with markedly elevated IL-2, IL-4, tumor necrosis factor-, and IFN-. The reason for this unusually reactive response is unknown. With the exception of patients 25 and 29 who showed marked elevations in both tumor necrosis factor- and IL-4, there were no substantial changes in these or other cytokines in any other patients.
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Pharmacokinetic data reported here are in general agreement with those reported by Goss et al. (15), where OSI-7836 was given by a 30-minute infusion (100-600 mg/m2). In that study, the median plasma clearance following the initial dose was 34.0 L/m2, with a median elimination half-life of 46.0 minutes; both values are similar to the plasma clearance of 36.2 L/m2 and half-life of 48.3 minutes determined in this study. However, in that study, a significant difference in elimination half-life between genders was observed with a median of 48.3 minutes (range, 43.2-58.3 minutes) for males and 42.6 minutes (range, 35.0-49.3 minutes) for females. Although there was a similar trend in this study, with a median of 48.9 minutes (range, 38.8-64.8 minutes) for males and 46.0 minutes (range, 22.6-53.5 minutes) for females, the difference was not statistically significant. In either case, the difference observed is not considered clinically relevant.
Fatigue, which has been associated with inflammatory cytokine production (20, 21), was the most frequent DLT in this study. The mechanism of this is unclear. An in-depth preclinical exploration of the potential mechanism of the observed fatigue was done at OSI Pharmaceuticals (22). First, at 10 µmol/L OSI-7836, there was no inhibition of a battery of receptors thought to be associated with fatigue, including adenosine; T4; adrenocorticorticotropic hormone; dopamine; -aminobutyric acid; neuropeptides Y1 and Y2; serotonin; histamine receptors 1, 2, and 3; dopamine; and norepinephrine transporters. Second, whole-body autoradiography in mice showed no differences in distribution of OSI-7836 within the brain. Third, assessments for centrally mediated fatigue, which included cortisol and adrenocorticorticotropic hormone measurements in dogs, showed that although there was a slight apparent decrease in cortisol levels between baseline and 6 days after dosing in dogs given 12 mg/kg OSI-7836, fluctuations in cortisol levels in control dogs made these differences insignificant. Similar results were obtained for adrenocorticorticotropic hormone, suggesting there was at least not a dramatic change attributable to OSI-7836.
Lymphocyte depletion was observed in this study and in the Canadian study with OSI-7836 (15). Therefore, plasma samples from a subset of 21 patients from this study were analyzed for a battery of cytokines, both proinflammatory (IL-1 and tumor necrosis factor-), costimulatory for lymphocytes (IL-2 and IL-4), and immunomodulatory (IL-6 and IL-10). Doses of 200 mg/m2 of OSI-7836 produced clinically meaningful elevations of both IL-10 and IL-6 of up to 5-fold. These elevations were temporally related to reductions in circulating lymphocytes, particularly CD19+ and CD8+ subsets. Despite this, patients did not experience an increase in bacterial or viral infections, and only four patients experienced mild reactivation of herpes simplex. However, the appearance of flu-like symptoms at 24 to 48 hours closely follows the spike in both cytokines.
IL-2, IL-4, tumor necrosis factor-, and IFN- were not elevated in 19 of 21 patients and therefore were not associated with changes in lymphocyte subsets. Although the lowest dose of 100 mg/m2 was associated with normal cytokine homeostasis, two of five patients still experienced dose-limiting fatigue, suggesting that either stimulation of cytokines by OSI-7836 is unrelated to fatigue or that repeated weekly dosing abrogates the potential benefit of dose reduction on fatigue.
These results confirm previous data that lymphocyte counts are reduced for up to 2 weeks following a single dose of OSI-7836 (15). In the present study, T-cell numbers remained at 80% of baseline and returned to baseline by day 7, whereas B-cell numbers remained suppressed for a longer period and only began to normalize by day 21. Even a low dose of 100 mg/m2 OSI-7836 weekly maintained B cells at around 20% of baseline with virtually no effect on T-cell numbers. This feature, combined with the absence of myelotoxicity and with fatigue being the only DLT, makes it interesting to speculate whether this nucleoside analogue might have activity in B-cell leukemia or lymphoma with a different toxicity profile than the commonly used and myelosuppressive fludarabine.
The mechanism of acute tumor pain and inflammation observed in patient 14 with mesothelioma is unclear. Analysis of his lymphocyte subsets and cytokines in plasma following treatment did not reveal a pattern, which would suggest immune response as a cause for the observed tumor pain.
Although no objective responses were seen in this study, there was some evidence of disease stabilization in patients with bladder cancer and mesothelioma, consistent with tumor types where gemcitabine has activity (19, 23–26). However, the stabilization was usually of relatively short duration, and continued treatment was limited by toxicity. It is noted that doses used in preclinical testing were often sufficient to cause myelosuppression, in distinct contrast to the clinical experience where, with the exception of lymphopenia, there was an absence of significant hematologic toxicity. Thus, it may be suggested that the lack of antitumor activity seen in this trial and indeed the report by Goss et al. (15) may be due to the inability to administer OSI-7836 at sufficiently high doses due to the early onset of dose-limiting fatigue.
This study has shown that OSI-7836 given either three times per week or weekly for 4 of 6 weeks to be associated with significant nonhematologic toxicity. However, given the potentially selective effect on B lymphocytes, there is possible interest in exploring this compound further in specific hematologic malignancies.
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Received 9/ 2/05; revised 2/ 4/06; accepted 2/21/06.
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