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© 2001 American Society for Clinical Oncology Troxacitabine, A Novel Dioxolane Nucleoside Analog, Has Activity in Patients With Advanced LeukemiaFrom the Departments of Leukemia and Biomathematics, The University of Texas M.D. Anderson Cancer Center, Houston; Department of Clinical Research, Institute for Drug Development, San Antonio, TX; and BioChem Pharma Inc, Laval, Quebec, Canada. Address reprint requests to Francis J. Giles, MD, The University of Texas M.D. Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd, Box 61, Houston, TX 77030-4095; email: frankgiles@ aol.com.
PURPOSE: To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m2/d (3.6 mg/m2/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined. RESULTS: Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m2/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m2. Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease. CONCLUSION: Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.
DESPITE PROGRESS IN leukemia therapy, most adult patients still die from disease progression. The cure rate in acute myeloid leukemia (AML) is 20% to 30%, and the cure rate in acute lymphocytic leukemia (ALL) is 25% to 40%.1,2 Hence, there is a need to identify new agents with antileukemic efficacy. Nucleoside analogs, eg, cytarabine (ara-C) and fludarabine, are among the most active, broad-spectrum antileukemic agents available.2-4 Naturally occurring nucleosides and all nucleoside analogues previously specifically developed for the treatment of cancer were in the -D configuration.5 Until recently, it was thought that the corresponding L-enantiomers would be ineffective since they were felt not to be recognized by activating metabolic enzymes. The discovery that the L-enantiomers of several dideoxycytidine analogues (eg, 3TC) were active against viruses including HBV and HIV was the first indication that L-nucleoside analogues may have therapeutic potential.6-8 The exchange of the sulfur endocyclic atom with an oxygen in the structure of 3TC resulted in the formation of L-(-)-OddC (troxacitabine, BCH-4556) ( Fig 1).5 Unlike 3TC, troxacitabine has substantial cytotoxic activity.9-12
As with ara-C, deoxycytidine kinase (dCK) catalyses the monophosphorylation of troxacitabine, thereby indicating that dCK may lack chiral specificity.9,11 In contrast, deoxycytidine deaminase (dCD) is more specific to chirality and is incapable of deaminating troxacitabine to its inactive form. This is in contrast to ara-C, which is inactivated via enhanced deamination in certain resistant tumors.13 As ara-C is one of the more potent single antileukemic agents, and troxacitabine may potentially be active in ara-C resistant leukemias, we carried out a phase I and pharmacokinetic study of troxacitabine in patients with advanced leukemia. The starting dose and schedule were chosen based on the overall toxicities and specifically on the pattern and degree of myelosuppression seen in solid tumor phase I studies of troxacitabine.14-17
Patient Eligibility Patients with refractory MDS (RAEB, RAEB-T, or CMML), AML, ALL, or CML-BP were eligible. Eligibility criteria were as follows: age older than 15 years; ECOG performance score of  2; serum bilirubin of 1.5 mg/dL; AST or ALT levels less than three times upper limit of normal (ULN) or less than five times the ULN if considered caused by tumor; serum creatinine 1.5 mg/dL; and no chemotherapy and/or radiation therapy for 2 weeks before entering this study with recovery from the toxic effects of that therapy. Patients with AML or ALL included were receiving first salvage with primary refractory disease or a first CR duration of less than 12 months, or patients receiving second or subsequent salvage therapy. Once an MTD was defined, eight further AML patients were treated to better define the agent’s toxicity. All patients gave signed informed consent indicating that they were aware of the investigational nature of this study in keeping with the policies of the M.D. Anderson Cancer Center.
Treatment
Pharmacokinetic Methods On day 1, urine was collected continuously in plastic containers at baseline and during the following collection intervals: 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 hours (on day 6 only). For each collection interval, the total volume of urine was recorded, and a 20-mL aliquot was frozen at -20°C until the time of analytic analysis. Analytic assay. A validated analytic assay consisting of high performance liquid chromatography and tandem mass spectrometric detection (LC/MS/MS) was used to determine concentrations of troxacitabine in plasma and urine samples. The LC/MS/MS consisted of a 1090 Series II Liquid Chromatograph (Hewlett Packard, Palo Alto, CA) coupled with an API 300 MS/MS Detector (PE SCIEX, Foster City, CA). A structural troxacitabine analog, BCH-189, was used as the internal standard. After spiking plasma and urine samples with BCH-189, troxacitabine was extracted from each matrix by vortexing with 25-mmol/L ammonium formate buffer at pH 3.5. The samples were loaded on preconditioned PRS cartridges (200mg/3mL; Varian, Walnut Creek, CA) and centrifuged at 800 rpm at 20°C for 2 minutes. After washing the cartridges with water and centrifugation at 800 rpm for 2 minutes, samples were eluted with 1% ammonium hydroxide in methanol and centrifuged at 600 rpm for 5 minutes. The organic solvent was evaporated to dryness in a Turbo Vap at 35°C, the final residue was reconstituted with 80/20 (v/v) acetonitrile/25 mmol/L ammonium acetate, and 5 µL was injected onto the LC system. The chromatographic conditions consisted of an Amino 5.0 cm x 40 mm, 3 µ analytic column, a mobile phase of 90/10 (v/v) acetonitrile/25 mmol/L ammonium acetate, and a flow rate of 1 mL/min. Samples were analyzed in the positive ion mode. Ionization was performed using a heated nebulizer (atmospheric pressure chemical ionization) inlet operating at 480°C with nebulizer gas pressure of 80 psi. The instrument monitored the multiple reaction monitoring (MRM) transition 214.0, more than 112.0 m/z and 230.2, more than 112.0 m/z for BHC-4556 and BCH-189, respectively. In plasma, the concentrations for the calibration curves ranged from 0.60 to 99.9 ng/mL. Samples with concentrations greater than the highest calibrator were diluted in prescreened free of interference human plasma. For quality control samples of troxacitabine in plasma prepared at low, medium, high, and at the assay limit of quantitation, the intra-assay precision (coefficient of variation) and accuracy (bias as percentage of nominal) ranged from 3.9% to 10.3% and 101.4% to 115.2%, respectively; the inter-assay precision and accuracy ranged from 3.5% to 8.6% and 95.9% to 118.3%, respectively. In urine, the concentrations for the calibration curves ranged from 10.1 ng/mL to 5,053.7 ng/mL. For quality control samples of troxacitabine in urine, the intra-assay precision and accuracy ranged from 3.3% to 23.2% and 84.3% to 101.9%, respectively; the inter-assay precision and accuracy ranged from 2.9% to 10.0% and 96.9% to 105.6%, respectively. Troxacitabine in plasma and urine is stable at -20°C for 8 months.
Pharmacokinetic and Statistical Analysis Pharmacokinetic parameters were summarized using descriptive statistics. Univariate correlation analysis was used to assess the relationship between troxacitabine dose and exposure (Cmax and AUC). Univariate correlation analysis of variance was used to characterize relationships between (1) troxacitabine dose and pharmacokinetic parameters (eg, clearance) and (2) troxacitabine exposure (eg, Cmax and AUC) and NCI grade of nonhematologic toxicity. The a priori level of significance was set at 0.05. Statistical analysis was performed using the JMP Version 3.1 statistical software program (SAS Institute, Cary, NC).
Response and Toxicity Criteria
The characteristics of the 42 patients treated on study (enrolled between July 1998 and June 1999) are listed in Table 1. Their median age was 61 years (range, 23 to 79 years), and performance status was 0 or 1 in 31 patients (74%). Thirty-one patients had AML. Troxacitabine was given as second salvage to 11 AML patients, third salvage to three patients, fourth or more salvage to two patients. Seventeen AML patients had never achieved a prior remission, and three had relapsed after allogeneic stem cell transplantation. Fifteen patients with AML received troxacitabine as their first salvage attempt: two after a first CR lasting less than 6 months, six with a first CR of 6 to 12 months, and seven with primary refractory disease. All patients with AML had previously received intermediate- or high-dose ara-C as part of induction, consolidation, or salvage therapy. Four patients with ALL were given troxacitabine as a second or subsequent salvage attempt for refractory disease, and one patient with refractory CML-BP received troxacitabine as a first salvage attempt. Dose levels were increased by 50% until grade 2 toxicities were seen, then by 25% to 33% depending on toxicities observed. The following dose levels were investigated: (mg/m2/d x 5 days) (1) 0.72, (2) 1.08, (3) 1.62, (4) 2.43, (5) 3.28, (6) 4.43, (7) 6, (8) 8, and (9) 10.
Toxicity The toxicities seen at each dose level are summarized in Table 2. DLT was defined at 8 mg/m2/d x 5 with two of two patients having dose-limiting grade 3 toxicities at 10 mg/m2 (stomatitis in one patient, hand foot syndrome in the second). We defined 8 mg/m2/d x 5 as the MTD and expanded the study at this dose level to treat a total of 11 patients. One patient of the first six patients treated at this dose level on developed grade 3 stomatitis at day 21 of first cycle of therapy; this resolved completely over a 7-day period. Three other patients had mild transient stomatitis. A further patient within the expanded cohort treated at this dose level developed grade 3 hand-foot syndrome. Five of 11 patients treated at this dose level had mild to moderate hand-foot syndrome. Moderate nausea/vomiting and diarrhea were seen in one patient each at this dose level. Five patients had fever with no overt infection at start of therapy, one patient had documented, stable, aspergillus otitis. Twenty-two patients had 31 febrile episodes during first course of therapy. These included 14 episodes of fever of unknown origin; seven pneumonias; six septicemic episodes; one skin cellulitis, and one combined CMV and parainfluenza pneumonia from which the patient fully recovered. Two patients had repeated stool cultures positive for vancomycin-resistant Enterococcus (VRE), and one patient had VRE septicemia.
Thirteen patients received a second course of troxacitabine that was begun at a median of 28 days (range, 21 to 83 days) after the start of course 1. One patient received a third course of troxacitabine that was begun 21 days after the start of course. Ten patients received a one–dose level increment with second course, three received the same dose, whereas one patient received a one–dose level decrement. During the second course of therapy, three (21%) of 14 patients developed grade 3 hand-foot syndrome, two further patients developed grade 2 hand-foot syndrome, one patient developed grade 3 stomatitis, and one patient developed grade 2 stomatitis.
Response
The single CML BP patient on study was treated at the 8-mg/m2 daily dose level and returned to chronic phase disease. All responses were to first course of therapy. None of the four patients with ALL showed a significant response. One patient was placed on the current study because of refractory MDS, which had developed against a background of multiple myeloma; the patient had received an autologous SCT before the diagnosis of MDS. The patient’s paraprotein had never been significantly reduced by his prior therapy, including by the autologous SCT. His paraprotein did fall significantly (by > 50%) after receipt of troxacitabine.
Troxacitabine Plasma Pharmacokinetics Mean plasma concentration-time profiles on days 1 and 5 at the 4.43-mg/m2 and 8.0-g/m2 dose levels are illustrated in Fig 2; plasma concentration data were available for three or more patients at these dose levels. An increase (shoulder) in the plasma concentration curve at 48 hours was observed; this suggests that troxacitabine may undergo hepatobiliary recirculation although further specific studies of this will be required. After termination of the 30-minute infusion on day 5, plasma troxacitabine concentrations remained above the assay limit of quantitation (LOQ) for 72 hours (day 8) in all patients. Troxacitabine concentrations measured on days 15 and 21 are summarized in units of nM in Table 6. On day 15, three of 11 samples were below the assay LOQ (BLQ); of the eight measurable concentrations, the mean value was 10.1 nmol/L (range, 3.4 to 17 nmol/L). On day 21, six of 11 samples were BLQ; of the six measurable concentrations, the mean value was 9.7 nmol/L (range, 0.35 to 19 nmol/L).
Troxacitabine pharmacokinetic parameters on days 1 and 5 are listed in Table 7 and Table 8, respectively. Cmax and AUC values increased in proportion with dose ( Fig 3) with strong linear correlations (R2 > 0.72). On day 1, the disposition of troxacitabine was dose-independent and characterized by mean (± SD) values for Vss and Cls of 71 (± 43) L and 170 (± 52) mL/min, respectively. After troxacitabine administration on the fifth day of treatment, the mean (± SD) t1/2 value was 82 (± 44) hours and Cls was reduced by approximately 20% with an average value of 137 mL/min. The mean (± SD) accumulation ratio was 1.3 (± 0.36).
Urinary Recovery of Troxacitabine Urine sampling was performed in 16 patients on day 1 and in 14 patients on day 5. Urine data was assessable for pharmacokinetic studies in 15 patients on day 1 and in 11 patients on day 5. An average of 41% and 54% of an administered troxacitabine dose was excreted as unchanged drug in the urine during the first 24 hours after treatment on days 1 and 5, respectively. (Table 7 and Table 8). An additional 15% of troxacitabine was excreted between 24 to 48 hours after administration of the fifth dose (Table 8). The majority of troxacitabine was excreted from time 0 to 12 hours after treatment ( Fig 4).
Troxacitabine Exposure-Toxicity Relationships Two patients experienced grade 3 nonhematologic toxicity during course 1 (grade 3 hand-foot syndrome in one patient treated at 8.0 mg/m2 and grade 3 stomatitis in one patient at 10 mg/m2) when pharmacokinetic studies were performed. Compared with the mean value of all observations (910 ng/mL·hr), AUC on day 5 was 1.8-fold and 2.8-fold higher in the patients that experienced grade 3 stomatitis or hand-foot syndrome, respectively ( Fig 5). No association between day 1 AUC and Cmax values on days 1 and 5 and toxicity were noted, with overlap in parameter values between the two patients experiencing grade 3 nonhematologic toxicity and those experiencing less than or equal to grade 2 nonhematologic toxicity. No association was noted between NCI grade of skin rash, which was less than or equal to grade 2 in all patients during course 1, and troxacitabine exposure.
Nucleoside analogs are a potent class of antineoplastic agents. In the hematologic malignancies a number of these agents, particularly ara-C and fludarabine, have established roles, whereas others such as compound 506U78 and clofarabine are under investigation.2,19 Troxacitabine is the first nucleoside L-enantiomer with substantial cytotoxic activity.9,11,12 Troxacitabine undergoes phosphorylation to its mono-, di, and triphosphate forms and is incorporated into DNA but not RNA.20 The triphosphate of troxacitabine is a good substrate for replicative and repair DNA polymerases in vitro.20 Although inhibition of such DNA polymerases could in part explain the cytotoxicity of troxacitabine, further evidence has indicated that troxacitabine is a complete DNA chain terminator. This can be rationalized since the dioxolane ring from the nucleoside structure lacks the necessary hydroxyl moiety for chain elongation. Furthermore, the cytotoxicity of troxacitabine against DU-145 prostate tumor cells directly correlated with the amount of troxacitabine monophosphate present in DNA terminals.11 Chain excision of integrated monophosphate occurs slowly and is not mediated by polymerase associated exonuclease. Consequently, the incorporation of troxacitabine triphosphate into DNA may be the major cytotoxic mechanism. We did not investigate intracellular pharmacokinetics on this study; this would be an interesting component of future studies in leukemia patients who have relatively easily accessible tumor cells. Deoxycytidine kinase (dCK) catalyses the monophosphorylation of both Ara-C and troxacitabine, indicating that dCK lacks chiral specificity.9 Deoxycytidine deaminase (dCD) is more chiral specific and cannot deaminate troxacitabine to its inactive form, in contrast to ara-C and gemcitabine. Other unique mechanistic features of troxacitabine relate to its cellular uptake and metabolism. In human prostate carcinoma DU-145, troxacitabine is transported rapidly into cells by both equilibrative sensitive and insensitive nucleoside transport systems.11 The monophosphates, diphosphates, and triphosphates of troxacitabine accumulate in a time- and concentration-dependent manner. Troxacitabine diphosphate is the major metabolite and its formation increases linearly with increasing extracellular drug concentration.21 This is different from ara-C, which lacks proportionality between ara-CTP formation and extracellular ara-C concentration.13 Troxacitabine does not inhibit ribonucleotide reductase.11 This indicates that troxacitabine may be mechanistically complementary to several nucleosides that are cytotoxic via ribonucleotide reductase inhibition. In this leukemia phase I study we established a troxacitabine dose of 8 mg/m2 daily for 5 days as MTD with stomatitis and hand-foot syndrome as DLTs. Other extramedullary toxicities included skin rashes which were generally mild, moderately itchy, involved the arms and trunk, and resolved completely with rapid recovery from attributable symptoms on a 3 day course of 10 mg to 20 mg daily of oral prednisone. The hand-foot syndrome tended to occur in second courses of therapy even when the interval between courses was prolonged. The typical hand-foot syndrome seen was markedly more pronounced in the hands than feet and usually consisted of skin erythema, itching, and mild periarticular soft tissue swelling associated with a sensation of skin tightness. These signs and symptoms typically resolved over a 3- to 5-day period. In those patients with grade 3 hand-foot syndrome, painful skin blistering and desquamation occurred with moderate limitation in hand movements and walking–these signs and symptoms typically took 5 to 7 days to resolve. Pyridoxine, and more recently, topical DMSO, have been proposed as being of value in alleviating the hand-foot syndrome toxicity of other agents, and may be worth including in future troxacitabine studies.22,23 The pharmacokinetic behavior of troxacitabine is substantially different from that of other nucleoside analogs possessing a D configuration, which are characterized by rapid disappearance from plasma due to deamination. In contrast, troxacitabine exhibited a long terminal half-life (82 hours) and a systemic clearance comparable to the glomerular filtration rate (137 mL/min). Consistent with the latter observation, the majority of troxacitabine was excreted as unchanged drug in the urine (69%). In addition, troxacitabine concentrations of approximately 10 nmol/L were measurable on days 15 and 21 in some patients (Table 6). These concentrations are in the range of those shown to have growth inhibitory activity in vitro in a variety of human normal and tumor cell lines (5 to 150 nmol/L).9
The association between the incidence of severe ( Troxacitabine had significant activity in this study group of patients with refractory leukemia. Three patients with AML achieved CR, a fourth had PR. The patient with CML-BP returned to chronic phase and remains in second chronic phase on pegylated interferon and ara-C therapy. Twenty two of 30 (73%) evaluable AML patients achieved marrow hypocellularity beyond day 14 of first course of therapy (Table 3), further indicating that troxacitabine has significant antileukemic activity. Estey et al have published a model based on 206 patients who received chemotherapy without stem cell transplantation for relapsed or primary refractory AML excluding acute promyelocytic leukemia, at the MD Anderson between 1991 and 1994.24 This model recognizes 4 groups: 1) Patients with an initial CR duration in excess of 2 years who are receiving 1st salvage attempt; 2) Patients with an initial CR duration of 1-2 years who are receiving their 1st salvage attempt; 3) Patients with the first CR duration lasting less than 1 year or with no initial CR who are receiving their initial salvage attempt and 4) Patients with an initial CR under 1 year or with no initial CR who are receiving a second or subsequent salvage therapy having not responded to a first salvage attempt. These 4 groups have anticipated CR rates of approximately 60 to 70%, 40 to 50%, 10 to 20%, and 0-1% respectively. In Table 1, we give the expected CR rate based on this model for the AML patients on this study. However, it must be emphasized that as both front line and relapsed regimens change, so may the ability of a prognostic schema such as this to stratify refractory AML patients be impaired. Although stratifying refractory AML patients into these different groups potentially increases the number of patients necessary for phase II studies, Bayesian prephase II selection designs may effectively address the issue of sample size.25-27 Although none of the four very heavily pretreated ALL patients responded, further investigation of troxacitabine is indicated in less refractory ALL patients. Further studies will define the activity of this agent in a better prognosis cohort of AML patients, eg, those with an initial CR duration of greater than one year and in patients in CML-BP. Combinations of troxacitabine with idarubicin, ara-C and topotecan will also be investigated. Troxacitabine will also be assessed in patients with myeloma and other lymphoproliferative disorders.
1. Cortes JE, Kantarjian H, Freireich EJ: Acute lymphocytic leukemia: a comprehensive review with emphasis on biology and therapy. Cancer Treat Res 84: 291-323, 1996[Medline]
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Estey EH, Thall PF, Pierce S, et al: Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/- all-trans retinoic acid +/- granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Blood 93: 2478-2484, 1999 3. Burnett AK: Tailoring the treatment of acute myeloid leukemia. Curr Opin Hematol 6: 247-252, 1999[Medline] 4. McCarthy AJ, Pitcher LA, Hann IM, et al: FLAG (fludarabine, high-dose cytarabine, and G-CSF) for refractory and high-risk relapsed acute leukemia in children. Med Pediatr Oncol 32: 411-415, 1999[Medline] 5. Mansour TS, Jin H, Wang W, et al: Anti-human immunodeficiency virus and anti-hepatitis-B virus activities and toxicities of the enantiomers of 2&|;-deoxy-3&|;-oxa-4&|;-thiocytidine and their 5-fluoro analogues in vitro. J Med Chem 38: 1-4, 1995[Medline] 6. Balzarini J, Wedgwood O, Kruining J, et al: Anti-HIV and anti-HBV activity and resistance profile of 2&|;,3&|;-dideoxy- 3&|;-thiacytidine (3TC) and its arylphosphoramidate derivative CF 1109. Biochem Biophys Res Commun 225: 363-369, 1996[Medline] 7. Mar EC, Chu CK, Lin JC: Some nucleoside analogs with anti-human immunodeficiency virus activity inhibit replication of Epstein-Barr virus. Antiviral Res 28: 1-11, 1995[Medline]
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Siu LL, Attardo G, Izbicka E, et al: Activity of (-)-2&|;-deoxy-3&|;-oxacytidine (BCH-4556) against human tumor colony-forming units. Ann Oncol 9: 885-891, 1998
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Grove KL, Cheng YC: Uptake and metabolism of the new anticancer compound beta-L-(-)- dioxolane-cytidine in human prostate carcinoma DU-145 cells. Cancer Res 56: 4187-4191, 1996
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Kadhim SA, Bowlin TL, Waud WR, et al: Potent antitumor activity of a novel nucleoside analogue, BCH-4556 (beta-L-dioxolane-cytidine), in human renal cell carcinoma xenograft tumor models. Cancer Res 57: 4803-4810, 1997 13. Grant S: Ara-C: cellular and molecular pharmacology. Adv Cancer Res 72: 197-233, 1998[Medline] 14. Belanger K, Moore M, Siu L, et al: A phase 1 study of the L-nucleoside analogue beta-L-dioxolan-cytidine (BCH-4556) given as a 30 minute infusion every 21 days. Proc Am Soc Clin Oncol 18: 197a, 1999 (abstr 760) 15. Baker SD, Stephenson J Jr, Goetz A, et al: Determinants affecting beta-L-dioxolan-cytidine (BCH-4556) exposure and relationship with toxicity in Phase 1 trials. Proc Am Soc Clin Oncol 18: 197a, 1999 (abstr 758) 16. Canova A, Yee L, Baker SD, et al: A phase 1 and pharmacokinetic study of beta-L-dioxolan-cytidine (BCH-4556) administered weekly for three weeks every 28 days. Proc Am Soc Clin Oncol 18: 197a, 1999 (abstr 759) 17. Stephenson J Jr, Baker SD, Johnson T, et al: A phase 1 and pharmacokinetic study of beta-L-dioxolan-cytidine (BCH-4556), an L-nucleoside antimetabolite on a daily x 5-day every 3-week schedule. Proc Am Soc Clin Oncol 18: 198a, 1999 (abstr 761) 18. Gibaldi M, Perrier D: Pharmacokinetics ( ed 2 ). New York, NY, Marcel Dekker, 1982 19. Keating MJ: Leukemia: A model for drug development. Clin Cancer Res 3: 2598-2604, 1997[Abstract]
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Kukhanova M, Liu SH, Mozzherin D, et al: L- and D-enantiomers of 2&|;,3&|;-dideoxycytidine 5&|;-triphosphate analogs as substrates for human DNA polymerases: Implications for the mechanism of toxicity. J Biol Chem 270: 23055-23059, 1995 21. Moore LE, Boudinot FD, Chu CK: Preclinical pharmacokinetics of beta-L-dioxolane-cytidine, a novel anticancer agent, in rats. Cancer Chemother Pharmacol 39: 532-536, 1997[Medline] 22. Vukelja SJ, Lombardo FA, James WD, et al: Pyridoxine for the palmar-plantar erythrodysesthesia syndrome. Ann Intern Med 111: 688-689, 1989 23. Lopez AM, Wallace L, Dorr RT, et al: Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia. Cancer Chemother Pharmacol 44: 303-306, 1999[Medline]
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Estey E, Kornblau S, Pierce S, et al: A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. Blood 88: 756, 1996 (letter) 25. Thall PF, Estey EH: A Bayesian strategy for screening cancer treatments prior to phase II clinical evaluation. Stat Med 12: 1197-1211, 1993[Medline] 26. Estey E, Thall P, David C: Design and analysis of trials of salvage therapy in acute myelogenous leukemia. Cancer Chemother Pharmacol 40: S9-12, 1997 27. Estey EH: Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia 14: 476-479, 2000[Medline] Submitted April 24, 2000; accepted September 18, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
z, which was determined from the slope of the terminal phase of the plasma concentration-time curve. A weighting factor of 1/C2 was used. Systemic clearance (Cls) was calculated by dividing the dose by AUC[inf] on day 1 and by AUC[0-24 hours] on day 5. The accumulation ratio was calculated as the day 5 to day 1 AUC ratio (AUC[0-24 hours]:AUC[inf]). The terminal half-life (t1/2) was determined following treatment with the fifth dose of troxacitabine, and was calculated as 0.693 divided by 
= 1 patient at 8.0 mg/m2 level with grade 3 hand-foot syndrome (AUC = 2,537 ng/mL*hr). 
= 1 patient at 10.0 mg/m2 with grade 3 stomatitis (AUC = 2,081 ng/mL*hr).
grade 3) hand-foot syndrome and stomatitis during course 1 and troxacitabine exposure were explored. Troxacitabine AUC was significantly higher (1.8- to 2.eight-fold) in two patients who experienced grade 3 stomatitis or hand-foot syndrome during course 1 than those who did not. The relationship between elevated troxacitabine AUC and severe nonhematologic toxicity remains to be demonstrated prospectively in a larger number of patients. Such relationships could be used to reduce troxacitabine doses early in the 5-day course of treatment to avoid elevated exposure (AUC) and toxicity. Alternatively, given that renal excretion is the principal route of troxacitabine clearance, individualized dosing strategies based on renal function could be formulated to potentially minimize excessive toxicity. 
