Phase II Study of Troxacitabine, a Novel Dioxolane Nucleoside Analog, in Patients With Refractory Leukemia

Giles, Francis J.; Garcia‐Manero, Guillermo; Cortes, Jorge; Baker, Sharyn D.; Miller, Carol B.; O’Brien, Susan; Thomas, Deborah A.; Andreeff, Michael; Bivins, Carol; Jolivet, Jacques; Kantarjian, Hagop M.

doi:10.1200/jco.20.3.656

Cited by 50 publications

(28 citation statements)

References 32 publications

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“…Alternatives to allogeneic SCT include using imatinib mesylate in combination with established regimens, eg, idarubicin and cytarabine in standard or in modified lower-dose schedules, or with investigational agents such as low-dose decitabine, troxacitabine, or homoharringtonine. [24][25][26][27] In our preliminary experience, troxacitabine produced objective responses in 5 of 16 evaluable patients (31%) and was associated with a median survival of 14 months. 24 If these findings can be confirmed in a larger study group, a combination regimen of imatinib mesylate and troxacitabine may prove beneficial.…”

Section: Discussionmentioning

confidence: 99%

“…[24][25][26][27] In our preliminary experience, troxacitabine produced objective responses in 5 of 16 evaluable patients (31%) and was associated with a median survival of 14 months. 24 If these findings can be confirmed in a larger study group, a combination regimen of imatinib mesylate and troxacitabine may prove beneficial. In other studies, the DNA-methylation inhibitor decitabine, given at 500 to 1000 mg/m 2 per course, produced an objective response rate of 28% and a median survival of 7 months.…”

Section: Discussionmentioning

confidence: 99%

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Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase

Kantarjian

Cortes

O’Brien

et al. 2002

Blood

263

144

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Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph ؉ below 35%], and 4 minor [Ph ؉ , 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P ‫؍‬ .001), longer median survival (7 versus 4 months, P ‫؍‬ .04), and lower 4-week induction mortality (4% versus 15%, P ‫؍‬ .07).Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML. (Blood. 2002;99:3547-3553)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase

Kantarjian

Cortes

O’Brien

et al. 2002

Blood

263

144

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“…It was shown in clinical evaluations to be effective against both leukemias and solid tumors. Phase II clinical studies have shown that L-OddC has significant antileukemic activity in patients with acute myeloid leukemia and chronic myelogenous leukemia in the blastic phase (5) and modest activity in advanced pancreatic adenocarcinoma (6), renal cell carcinoma (7), and nonsmall cell lung carcinoma (8). It is currently under consideration for beginning phase I/II clinical trials for the treatment of solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma

Lam

Bussom²,

Cheng³

2009

Molecular Cancer Therapeutics

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B-L-Dioxolane-cytidine (L-OddC; BCH-4556; troxacitabine), a novel L-configuration deoxycytidine analogue, was under clinical trials for treating cancer. The cytotoxicity of L-OddC is dependent on its phosphorylation to L-OddCTP by phosphoglycerate kinase (PGK) and its subsequent addition into nuclear DNA. Because PGK is induced with hypoxia, the expression of hypoxia-inducible factor-1A and PGK of H460 cells (human non-small cell lung carcinoma) in vitro and in vivo was studied. In culture, hypoxic treatment induced the protein expression of PGK by 3-fold but had no effect on the protein expression of other L-OddC metabolism-associated enzymes such as apurinic/apyrimidinic endonuclease-1, deoxycytidine kinase, CMP kinase, and nM23 H1. Using a clonogenic assay, hypoxic treatment of H460 cells rendered cells 4-fold more susceptible to L-OddC but not to gemcitabine (dFdC) following exposure to drugs for one generation. Using hypoxia response element-luciferase reporter system, Western blotting, and immunohistochemistry, it was found that hypoxiainducible factor-1A and PGK expression increased and could be correlated to tumor size. Despite dFdC being more toxic than L-OddC in cell culture, L-OddC (300 mg/kg i.p.) had a stronger antitumor activity than dFdC in H460 xenograft-bearing nude mice. Furthermore, L-OddC

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“…infusion for 30 minutes daily for 5 days showed significant antineoplastic activity in patients with relapsed myeloid leukemias, with the principal toxicities being grade 3 or 4 stomatitis, hand-foot syndrome, and skin rash (12)(13)(14). Troxacitabine was also evaluated as a 30-minute infusion in patients with advanced solid malignancies on various administration schedules, including daily for 5 days every 3 to 4 weeks, weekly for 3 of 4 weeks, and once every 21 days, where the dose-limiting toxicity was neutropenia, and the most frequent nonhematologic toxicities were skin rash and hand-foot syndrome (15)(16)(17).…”

mentioning

confidence: 99%

“…Plasma exposure toxicity assessments in patients with refractory leukemia receiving 30-minute infusions showed that elevated troxacitabine plasma area under the concentration-time curve was related to the severity of mucositis and hand-foot syndrome (13).…”

mentioning

confidence: 99%

Population Pharmacokinetics of Troxacitabine, a Novel Dioxolane Nucleoside Analogue

Lee

Rowinsky²,

Li³

et al. 2006

Clinical Cancer Research

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Purpose: To develop and validate a population pharmacokinetic model for troxacitabine, a novel L-nucleoside analogue, administered by short infusion; to characterize clinical covariates that influence pharmacokinetic variability; and to design a dosage rate for continuous infusion administration to achieve low micromolar concentrations, which may be more efficacious than shorter infusions. Experimental Design: Plasma samples from 111 cancer patients receiving troxacitabine (0.12-12.5 mg/m 2 ) as a 30-minute infusion in phase I trials were used to develop the model with NONMEM. Clinical covariates evaluated included creatinine clearance, body surface area, age, and sex. From the model, a troxacitabine dosage rate of 2.0 to 3.0 mg/m 2 /d was expected to achieve a target concentration of 0.1 Amol/L; plasma samples were obtained during the infusion from eight patients receiving troxacitabine as a 3-day infusion. Results:Troxacitabine pharmacokinetics were characterized by a three-compartment linear model. The mean value for systemic clearance [interindividual variability (CV%)] from the covariatefree model was 9.1 L/h (28%). Creatinine clearance and body surface area accounted for 36% of intersubject variation in clearance. Troxacitabine 2.0 mg/m 2 /d (n = 3) and 3.0 mg/m 2 /d (n = 5) for 3 days produced mean F SD end of infusion concentrations of 0.12 F 0.03 and 0.15 F 0.03 Amol/L, respectively. Conclusions: Renal function and body surface area were identified as sources of troxacitabine pharmacokinetic variability. The population pharmacokinetic model model^derived dosage rates for continuous infusion administration successfully achieved predetermined target plasma concentrations.The present model may be used to optimize treatment with troxacitabine by developing a dosing strategy based on both renal function and body size.

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Phase II Study of Troxacitabine, a Novel Dioxolane Nucleoside Analog, in Patients With Refractory Leukemia

Abstract: Troxacitabine has significant antileukemic activity in patients with AML and CML-BP.

Cited by 50 publications

References 32 publications

Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase

Imatinib mesylate (STI571) therapy for Philadelphia chromosome–positive chronic myelogenous leukemia in blast phase

Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma

Population Pharmacokinetics of Troxacitabine, a Novel Dioxolane Nucleoside Analogue

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