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Originally published as JCO Early Release 10.1200/JCO.2006.06.6209 on December 4 2006 © 2007 American Society of Clinical Oncology. Phase I/II Study of Continuous-Infusion Troxacitabine in Refractory Acute Myeloid Leukemia
From the Weill Medical College of Cornell University, New York, NY; Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Pathology, University of California–San Diego; and SGX Pharmaceuticals, San Diego, CA Address reprint requests to Gail J. Roboz, MD, Weill Medical College of Cornell University, The New York Presbyterian Hospital, 520 East 70th St, Starr 340A, New York, NY 10021; e-mail: gar2001{at}med.cornell.edu
Purpose Troxacitabine is a non-natural nucleoside analog with unique structural and metabolic features. Bolus intravenous (IV) troxacitabine regimens have shown significant activity in patients with refractory acute myeloid leukemia (AML) and preclinical data suggest that administration via continuous infusion may result in enhanced antitumor activity. Patients and Methods Patients with refractory AML initially received troxacitabine 10.1 mg/m2 by continuous IV infusion (CIVI) for 48 hours. Infusion duration and daily dose were increased in subsequent patient cohorts. Results Forty-eight patients, median age 58 years (range, 21 to 81 years), were treated. Dose-limiting toxicities were mucositis and hand-foot syndrome, and 12.0 mg/m2/d for 5 days was established as the maximum-tolerated dose. Seven patients (15%) achieved complete remission (CR) or CR with incomplete platelet recovery (CRp), with a median survival among responders of 12 months. Steady-state concentrations of troxacitabine were found to be linearly and inversely proportionally related to calculated creatinine clearance at doses of 10.1 and 12.0 mg/m2/d. All patients responding to troxacitabine had steady-state serum drug concentration of more than approximately 80 ng/mL. In 27 patients achieving target troxacitabine plasma concentrations (ie, approximately 80 ng/mL) the CR + CRp rate was 26%. Conclusion Troxacitabine administered as a CIVI allows a significant increase in dose-intensity in comparison to IV bolus regimens, has antileukemic activity, and warrants additional investigation in patients with refractory AML. The recommended phase II study dose is 12.0 mg/m2 daily CIVI for 5 days.
Refractory acute myeloid leukemia (AML) is almost invariably fatal and new therapeutic strategies are needed. Nucleoside analogs are known to be potent, broad-spectrum antileukemic agents, but they are susceptible to inactivation.1 Troxacitabine is a novel L-enantiomer nucleoside with unique biologic properties and significant antileukemic activity in clinical trials.2-7 It has a distinct pattern of cellular uptake and metabolism and may not be susceptible to nucleoside-specific membrane transporters, an important mechanism of resistance to most nucleoside analogs.8 In addition, the pharmacokinetic behavior of troxacitabine is distinct from that of other D-nucleoside analogs, which disappear rapidly from plasma due to deamination. In contrast, troxacitabine is not a substrate for cytidine deaminase, and has a long terminal half-life of more than 80 hours and a systemic clearance comparable to the glomerular filtration rate, with approximately 70% of drug excreted unchanged in the urine.2 Previous clinical studies have demonstrated that troxacitabine administered via intravenous (IV) bolus is active in AML, myelodysplastic syndrome, and the myeloid blast phase of chronic myeloid leukemia.1-6,9 In a phase I study of leukemia patients, troxacitabine was administered as a 30-minute IV infusion daily for 5 days. The maximum-tolerated dose (MTD) was 8.0 mg/m2/d, with dose-limiting toxicities (DLT) of mucositis and hand-foot syndrome (HFS); skin rash was also observed frequently.2 Of 30 assessable AML patients, three attained complete remission (CR) and one had a partial remission (PR), for an overall response rate of 13%. In a subsequent phase II study of troxacitabine administered at the same MTD, there were two CRs and one PR (overall response rate, 18%) in 16 assessable AML patients.5 Troxacitabine was also active in refractory AML when combined with cytarabine (ara-C), idarubicin, and topotecan.3 Finally, in a randomized study of older AML patients with adverse karyotype, troxacitabine combined with ara-C was similar to conventional induction therapy with idarubicin plus ara-C with respect to efficacy and survival.6 Preclinical data suggest that continuous intravenous infusion (CIVI) of troxacitabine may be superior to bolus administration.10 Troxacitabine permeates cells slowly, by carrier-mediated diffusion, and 72-hour drug exposures are significantly more cytotoxic than 1-hour exposures. Xenograft experiments demonstrated further that tumor growth inhibition was observed after 6-day exposures to troxacitabine and antitumor activity persisted after the end of drug exposure. Although growth inhibition was observed after 3 days of drug exposure, maximum effect required at least 5 days. Prolonged exposures to low micromolar concentrations of troxacitabine lead to significant inhibition of tumor growth without the need to achieve peak drug concentrations.10 On the basis of these clinical and preclinical data, a phase I/II study of troxacitabine was initiated in patients with refractory AML. The objectives were to identify an optimal CIVI dosing schedule, characterize the pharmacokinetics, and make an initial assessment of efficacy.
Patient Eligibility This was a single-arm, multicenter, open-label, phase I/II study. Patients age  18 years with pathologically confirmed AML refractory to prior therapy were eligible. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance score of  2, estimated life expectancy more than 8 weeks, sterility or adequate contraception, serum bilirubin 2.0 mg/dL, AST and ALT levels less than 3x the upper limit of normal, serum creatinine 1.5 mg/dL, and more than 14 days from treatment with other investigational agents. Patients with uncontrolled, active infection or active CNS leukemia were ineligible. The protocol was approved by the institutional review boards of the participating institutions and all patients provided written informed consent.
Treatment
Response and Toxicity Criteria
Pharmacokinetics
Forty-eight patients were treated on study (Table 1). The median age was 58 years (range, 21 to 81 years). Forty-two (88%) patients had ECOG performance status 0 to 1 and six (12%) had ECOG performance status 2. Sixteen (33%) patients had poor-prognosis cytogenetics. Forty-one (85%) patients had an initial CR duration of less than 12 months. Seventeen patients were treated with first salvage therapy, 12 of whom had an initial CR duration of less than 6 months. Twenty-two patients were treated in second salvage therapy (44%) and nine (19%) were treated with third salvage therapy or beyond.
Toxicity Troxacitabine is myelosuppressive and most patients experienced grade 4 pancytopenia, as expected. Previous clinical studies have demonstrated that the most commonly observed troxacitabine-related extramedullary toxicities are rash, HFS, and mucositis.2-6 The rash is typically a localized, maculopapular eruption responsive to prednisone. HFS symptoms are on a spectrum ranging from palmar and plantar erythema to blistering and desquamation of the hands and feet. In this study, the infusion rate was fixed initially at 10.1 mg/m2/d and dose escalation was accomplished by increasing the number of days of infusion from 2 to 6. Thus, in successive cohorts, the cumulative doses ranged from 20.2 to 60.6 mg/m2. These doses were well tolerated over 5 days, but extension to 6 days resulted in increased grade 3 mucositis (Table 2). Dose reduction to 8.4 mg/m2/d was then attempted for 6 days, but grade 3 mucositis was still noted. Thus, it was determined that troxacitabine administered as a CIVI for 6 days was not well tolerated.
Subsequently, the CIVI duration was fixed at 5 days and the total daily dose was increased. At the 10.1 mg/m2/d for 5 days dose level, four patients experienced grade 2 HFS. On the basis of preliminary data suggesting that nicotine may improve symptoms of HFS in patients treated with capecitabine (L. Vahdat, personal communication, March 2003), a nicotine patch was applied to patients starting on day 1 of treatment. Doses of 12.0 mg/m2/d for 5 days were well tolerated, but 14.0 mg/m2/d for 5 days resulted in mucositis and HFS as DLTs in both treated patients. Based on these results, 12.0 mg/m2/d for 5 days was established as the MTD, and an additional cohort of 15 patients was treated at this dose. Grade 3 mucositis was observed in 13% of patients, HFS was observed in 6% of patients, and rash was observed in 4% of patients; there were no grade 4 events. Other grade 3 or 4 extramedullary toxicities observed in more than 10% of patients were neutropenic fever (80%), bacteremia (44%), hypophosphatemia (23%), hypokalemia (19%), edema (15%), dyspnea (10%), fatigue (10%), hypocalcemia (10%), and sepsis (10%).
Pharmacokinetics
Response This was a phase I trial, thus efficacy was not the primary end point. All patients were assessable for response, as summarized in Tables 3 and 4. Of the 48 patients treated, seven patients responded (five CR and two CR with incomplete platelet recovery), for an overall response rate of 15%. In the 41 patients who received cumulative doses of troxacitabine of 40.4 mg/m2 or higher, the response rate was 17%. In 27 patients who achieved the target troxacitabine concentration of more than approximately 80 ng/mL, the response rate was 26%. The median duration of survival was 12 months. One patient achieved marrow aplasia after troxacitabine (Css > 80 ng/mL) and underwent nonmyeloablative stem-cell transplantation before complete peripheral count recovery; the patient subsequently achieved CR. Clinical characteristics of the responders are listed in Table 5.
Troxacitabine is a novel nucleoside L-enantiomer with unique biologic properties and significant antileukemic activity in clinical studies.2-6,8,10-13 The objective of this study was to identify a phase II dosing regimen for troxacitabine administered via CIVI. The study population was a poor-prognosis group of heavily pretreated patients with AML, many of whom were age older than 60 years. The MTD by IV bolus was 8.0 mg/m2/d for 5 days,2 whereas the MTD by CIVI was 12.0 mg/m2/d for 5 days. As listed in Table 6, the change in administration of troxacitabine from IV bolus to CIVI allowed more drug to be administered with an improved toxicity profile, and possibly enhanced efficacy. In contrast, increased doses of cytarabine, another nucleoside analog with potent antileukemic activity, are well known to correlate with increased toxicity, especially neurotoxicity.14
This study clearly demonstrated the superiority of a CIVI administration schedule for troxacitabine. Furthermore, pharmacokinetic data showed a linear relationship between creatinine clearance and troxacitabine concentration. The target Css of 0.4 µmol/L (approximately 80 ng/mL) was achieved in 27 patients and the response rate in this group was 26%, higher than that of the study population as a whole. All patients responding to troxacitabine in this study achieved plasma concentrations of approximately 80 ng/mL or more. Pharmacokinetic analyses suggest that the 12.0 mg/m2/d dosing schedule is acceptable for patients with calculated creatinine clearance between 45 and 125 mL/min, which encompasses approximately 80% of adult AML patients. Additional data will be required to identify appropriate dosing schedules for patients with calculated creatinine clearance outside this range; follow-up clinical studies are ongoing. The identification of a reliable target plasma concentration of troxacitabine may allow real-time adjustments to accommodate clinical fluctuations and thus maximize efficacy. Conventional AML regimens are not typically dosed on the basis of area under the curve or other pharmacokinetic parameters. The adverse events observed in this study were, in general, as expected for myelosuppressive chemotherapy in a refractory AML population. Specific extramedullary toxicities attributable to troxacitabine were similar to those observed in previous clinical studies and included skin rash, mucositis, and HFS.2-6 No new extramedullary toxicities were identified with CIVI compared with bolus administration. The rash was generally a mild, localized, maculopapular erythematous eruption responsive to prednisone. Prophylactic administration of prednisone 25 mg daily did not completely eliminate the development of rash, but there were only two grade 3 events in the 48 patients treated. For patients receiving prophylactic prednisone who still developed rash, the dose was increased to 50 mg daily and then rapidly tapered, with resolution of symptoms. Mild HFS was characterized by skin erythema, periarticular soft-tissue swelling, and a sensation of skin tightness or itching. Patients who developed grade 3 HFS had painful skin blistering and desquamation, which, in some cases, caused significant but temporary impairment of hand movement and ambulation. It was hypothesized that nicotine patches could be helpful in preventing HFS via peripheral vasoconstriction, and anecdotal reports suggest a similar role in patients treated with capecitabine, a drug also known to cause HFS. The utility of nicotine patches for the prevention or amelioration of HFS caused by troxacitabine is unclear, but there were no episodes of grade 4 HFS after the implementation of the patches in this study. There currently is no established therapy for patients with refractory AML, who are generally resistant to conventional chemotherapy and have an extremely poor prognosis. Giles et al15 recently reviewed outcomes in 422 patients with second salvage therapy for AML. For 337 patients with first remission less than 12 months, the overall response rate was 2% and median survival was 2.1 months. For 85 patients with first remission more than 12 months, the overall response rate was 14%, with median survival 2.3 months among responders.15 Our study included patients with primary refractory AML as well as those who had received multiple salvage regimens. The response rate and duration are encouraging. In addition, although the goal for these patients is often allogeneic transplantation, the probability of successful transplantation in the setting of active leukemia is poor. Thus, the ability to induce remission in a refractory AML patient restores the possibility of curative therapy with transplantation. For selected patients, stem-cell transplantation may be feasible during marrow aplasia after chemotherapy, and it is notable that troxacitabine induced aplasia in 40% of the patients treated in this study. On the basis of these promising results, a multicenter phase II study of CIVI troxacitabine at 12.0 mg/m2/d for 5 days has been initiated in adult AML patients who require second salvage therapy for treatment of relapsed disease.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Michael J. Kelner, SGX Pharmaceuticals Stock: Michael J. Kelner, SGX Pharmaceuticals Honoraria: Francis J. Giles, SGX Pharmaceuticals Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Gail J. Roboz, Francis J. Giles, Eric J. Feldman Administrative support: Tania J. Curcio, Meredith A. Wilkes, S. Lani Park Provision of study materials or patients: Gail J. Roboz, Francis J. Giles, Ellen K. Ritchie, Hagop M. Kantarjian, Stefan Faderl, Farhad Ravandi, Eric J. Feldman Collection and assembly of data: Meredith A. Wilkes, S. Lani Park, Michael J. Kelner Data analysis and interpretation: Gail J. Roboz, Francis J. Giles, Michael J. Kelner, Eric J. Feldman Manuscript writing: Gail J. Roboz, Francis J. Giles, Michael J. Kelner, Eric J. Feldman Final approval of manuscript: Gail J. Roboz, Francis J. Giles, Michael J. Kelner, Eric J. Feldman Other: Sandra Allen-Bard, Tania J. Curcio (Clinical management of patients)
published online ahead of print at www.jco.org on December 4, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Giles FJ: Troxacitabine-based therapy of refractory leukemia. Expert Rev Anticancer Ther 2:261-266, 2002[CrossRef][Medline] 2. Giles FJ, Cortes JE, Baker SD, et al: Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia. J Clin Oncol 19:762-771, 2001 3. Giles FJ, Faderl S, Thomas DA, et al: Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias. J Clin Oncol 21:1050-1056, 2003 4. Giles FJ, Feldman EJ, Roboz GJ, et al: Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with untreated or imatinib mesylate-resistant chronic myeloid leukemia in blastic phase. Leuk Res 27:1091-1096, 2003[CrossRef][Medline] 5. Giles FJ, Garcia-Manero G, Cortes JE, et al: Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with refractory leukemia. J Clin Oncol 20:656-664, 2002 6. Giles FJ, Kantarjian HM, Cortes JE, et al: Adaptive randomized study of idarubicin and cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in untreated patients 50 years or older with adverse karyotype acute myeloid leukemia. J Clin Oncol 21:1722-1727, 2003 7. Alvarado Y, Kantarjian HM, Cortes JE, et al: Troxacitabine activity in extramedullary myeloid leukemia. Hematology 7:179-185, 2002[CrossRef][Medline] 8. Gourdeau H, Clarke ML, Ouellet F, et al: Mechanisms of uptake and resistance to troxacitabine, a novel deoxycytidine nucleoside analogue, in human leukemic and solid tumor cell lines. Cancer Res 61:7217-7224, 2001 9. Giles FJ: Novel agents for the therapy of acute leukemia. Curr Opin Oncol 14:3-9, 2002[CrossRef][Medline] 10. Gourdeau H, Genne P, Kadhim S, et al: Antitumor activity of troxacitabine (Troxatyl) against anthracycline-resistant human xenografts. Cancer Chemother Pharmacol 50:490-496, 2002[CrossRef][Medline] 11. Gourdeau H, Bibeau L, Ouellet F, et al: Comparative study of a novel nucleoside analogue (Troxatyl, troxacitabine, BCH-4556) and AraC against leukemic human tumor xenografts expressing high or low cytidine deaminase activity. Cancer Chemother Pharmacol 47:236-240, 2001[CrossRef][Medline] 12. Gourdeau H, Leblond L, Hamelin B, et al: Species differences in troxacitabine pharmacokinetics and pharmacodynamics: Implications for clinical development. Clin Cancer Res 10:7692-7702, 2004 13. 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 57:4803-4910, 1997 14. Giles FJ, Keating A, Goldstone AH, et al: Acute myeloid leukemia, in, Hematology. Washington, DC, American Society of Hematology, 2002, pp 73-110 15. Giles FJ, O'Brien S, Cortes J, et al: Outcome of patients with acute myelogenous leukemia after second salvage therapy. Cancer 104:547-554, 2005[CrossRef][Medline] Submitted March 15, 2006; accepted September 7, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
80 ng/mL (
) 12.0 mg/m2/d (P = .01).
