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© 2002 American Society for Clinical Oncology Phase II Study of Troxacitabine, a Novel Dioxolane Nucleoside Analog, in Patients With Refractory LeukemiaByFrom the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX; Johns Hopkins Oncology Center, Baltimore, MD; and Suire BioChem Inc, Laval, Quebec, Canada. Address reprint requests to Francis J. Giles, MD, University of Texas, M.D. Anderson Cancer Center, Department of Leukemia, 1400 Holcombe Blvd, Box 428, Houston, TX 77030; email: fgiles@ mdanderson.org.
PURPOSE: To investigate the activity of a novel dioxolane L-nucleoside analog, troxacitabine (L-(-)-OddC, BCH-4556), in patients with refractory leukemia. PATIENTS AND METHODS: Study participants were 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 provided as an intravenous infusion for more than 30 minutes daily for 5 days at a dose of 8.0 mg/m2/d (40 mg/m2 per course). Courses were given every 3 to 4 weeks according to antileukemic efficacy. RESULTS: Forty-two patients (AML, 18 patients; MDS, one patient; ALL, six patients; CML-BP, 17 patients) were treated. Median age was 51 years (range, 23 to 80 years); 22 patients were male. Stomatitis was the most significant adverse event, with three patients (7%) and two patients (5%), respectively, experiencing grade 3 or 4 toxicity. Ten patients (24%) had grade 3 hand-foot syndrome, and two patients (5%) had grade 3 skin rash. One patient (2%) had grade 3 fatigue and anorexia. Marrow hypoplasia occurred between days 14 and 28 in 12 (75%) of 16 assessable patients with AML. Two complete remissions and one partial remission (18%) were observed in 16 assessable patients with AML. None of six patients with ALL responded. Six (37%) of 16 assessable patients with CML-BP experienced a return to chronic-phase disease. CONCLUSION: Troxacitabine has significant antileukemic activity in patients with AML and CML-BP.
NEW AGENTS ARE REQUIRED to improve leukemia therapy. Some nucleoside analogs are active, broad-spectrum antileukemic agents.1-4 All naturally occurring nucleoside analogs and all nucleoside analogs in use as anticancer agents are in the D configuration.5 Nucleoside L-enantiomers were not developed because they were considered to be unrecognizable to activating metabolic enzymes. L-Enantiomers of several dideoxycytidine analogs (eg, lamivudine) were found to be potent antiviral agents, thus stimulating interest in the development of L-enantiomers as potential anticancer agents.6-9 Exchange of the sulfur endocyclic atom with an oxygen in the structure of lamivudine resulted in the formation of troxacitabine (L-(-)-OddC, BCH-4556; Troxatyl) (Fig 1).5 Troxacitabine has substantial cytotoxic activity.9-12 In a phase I study in 42 patients with advanced leukemia, stomatitis, and hand-foot syndrome, dose-limiting toxicities were evident.13 The maximum tolerated dose was defined as 8 mg/m2/d when troxacitabine was given as an intravenous infusion over the course of 30 minutes daily for 5 days. Marrow hypoplasia occurred between days 14 and 28 in 73% of 31 patients with acute myeloid leukemia (AML) on the phase 1 study. Three complete and 1 partial remission (13%) were observed in 30 assessable patients with AML; one patient with MDS experienced hematologic improvement, and the single patient with chronic myelogenous leukemia in blastic phase (CML-BP) experienced a return to chronic-phase disease.13 In view of this activity, we conducted a phase II study of troxacitabine in patients with advanced leukemia; we include those patients treated at the maximum tolerated dose on the phase I study within this analysis.
Patient Eligibility Patients with myeloid CML-BP or whose disease had failed to respond to prior therapy for myelodysplastic syndromes (MDS; refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomacrocytic leukemia), AML, or acute lymphocytic leukemia (ALL) were eligible. Eligibility criteria were as follows: age older than 15 years; Eastern Cooperative Oncology Group performance score of  2; serum bilirubin of 1.5 mg/dL; AST or ALT levels less than 3 times upper limit of normal or less than 5 times the upper limit of normal if considered due to tumor; serum creatinine 1.5 mg/dL; and no chemotherapy 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 those receiving salvage treatment for the first time with primary refractory disease or a first complete remission (CR) duration of less than 12 months, or patients receiving second or subsequent salvage therapy. Patients with CML-BP were eligible at time of diagnosis or if their disease had already failed to respond to therapy for CML-BP. 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
Response and Toxicity Criteria Toxicity was graded on a scale of 0 to 5 by using the National Cancer Institute Common Toxicity Criteria version 2.0. All patients who received at least one dose of troxacitabine were considered assessable for toxicity.
Systemic Exposure-Response Relationships Four AUC ranges were defined, as follows: (1) the first quartile (ie, AUC 262 ng/mL/h); (2) the second quartile (ie, AUC 263 to 710 ng/mL/h); (3) the third quartile (ie, AUC 711 to 1419 ng/mL/h); and (4) the fourth quartile (ie, AUC 1,420 ng/mL/h). The second and third quartiles were the interquartile range. The relationship between systemic exposure and response was evaluated by determining the percentage of patients whom experienced an oncolytic effect, or grade 3 stomatitis, hand-foot syndrome, or both at each range of AUC values. The data were initially evaluated by visual inspection of a plot of troxacitabine AUC range and response after one course of treatment, expressed as percentage of patients. The maximum effect (Emax) model was chosen as the mathematical model to describe oncolytic effect as follows: % patients with oncolytic effect = (Emax x AUCrange)/(AUCrange50 + AUCrange), where Emax or the maximal effect was fixed at 100% and AUCrange50 is the AUC range (or quartile) at which the effect is 50% of maximum. The Emax model was fitted to the data by nonlinear least-squares regression as implemented in the program Kaleidagraph (Synergy Software, Reading, PA). SE for the estimated parameter AUCrange50 and coefficient of determination (R2) were used to assess the goodness of fit.
The characteristics of the 42 patients treated on the study protocol (enrolled between June 1999 and September 2000) are listed in Table 1. Their median age was 51 years (range, 23 to 80 years), and performance status was 0 or 1 in 32 patients (76%). Eighteen patients (43%) had AML. Troxacitabine was given as the second salvage treatment to five patients (28%) with AML, the third salvage treatment to one patient (5%), and the fourth or more salvage treatment to one patient (5%). Four patients (22%) with AML had never experienced a prior remission. Eleven patients (61%) with AML received troxacitabine as their first salvage attempt, two after a first CR lasting less than 6 months, five with a first CR of 6 to 12 months, and four with a first CR of more than 12 months. All patients with AML had previously received high-dose cytarabine as part of induction, consolidation, or salvage therapy. Four patients with ALL were administered troxacitabine as a second or subsequent salvage attempt. Four (23%) of 17 patients with CML-BP received troxacitabine as a first salvage attempt; three of these patients experienced a second chronic phase. Six patients (35%) with CML-BP had disease that failed to respond to prior signal transduction inhibitor 571 (STI571) therapy for CML-BP; one of these patients experienced a second chronic phase. Thirteen patients with CML-BP had disease that failed to respond to prior therapy for blastic-phase disease; two had disease that failed to respond to STI571 as sole prior therapy for CML-BP.
The other 11 patients had disease that failed to respond to the following CML-BP therapies: (1) 2-chlorodeoxyadenosine (2CDA), cyclophosphamide/cytarabine/topotecan, and splenic radiation; (2) 6-thioguanine; (3) daunorubicin and cytarabine; (4) mitoxantrone/cytarabine and STI571; (5) idarubicin/cytarabine, 2CDA, cyclophosphamide/etoposide, STI571, and cyclophosphamide/vincristine/liposomal daunorubicin/dexamethasone; (6) STI571, clofarabine, and decitabine; (7) hydroxyurea, allogeneic stem-cell transplantation (SCT) (busulfan/cyclophosphamide [BuCy] conditioning), homoharringtonine, and liposomal daunorubicin/cytarabine; (8) mitoxantrone/cytarabine, STI571, and homoharringtonine; (9) cyclophosphamide/cytarabine/topotecan, topotecan/cytarabine, matched unrelated SCT (BuCy conditioning), second matched unrelated SCT (fludarabine/busulfan/antithymocyte globulin conditioning), STI571, and radiation to bone lesions; (10) topotecan/cytarabine; and (11) cyclophosphamide/vincristine/doxorubicin/dexamethasone, decitabine, and allogeneic SCT (BuCy conditioning) (Table 2).
Toxicity All 42 patients were assessable for toxicity and had received a total of 63 courses of treatment. Stomatitis was the most significant adverse event, with nine patients (21%), three patients (7%), and two patients (5%) having grade 2, 3, or 4 toxicity, respectively. Ten patients (24%) had grade 3 hand-foot syndrome; 14 patients (33%) grade 2 hand-foot syndrome. Twenty-four patients (57%) had grade 2 rash, and two patients (5%) had grade 3 rash. One patient (2%) had grade 3 fatigue and anorexia. Seven patients (17%) had grade 2 nausea. Five patients (12%) had grade 2 diarrhea. One patient (2%) had grade 2 hiccups. Three patients (7%) had alopecia. One patient (2%) had fever with no overt infection at start of therapy; nine patients (21%) had documented infections at the start of therapy. These patients were eligible for therapy because the infections were considered to be controlled by antimicrobial therapy at time of study entry. Eleven patients (26%) had no febrile episodes on therapy; 31 patients (74%) had 41 febrile episodes during first course of therapy. These included 14 episodes of fever of unknown origin; nine episodes of pneumonias; six episodes of septicemic episodes, including one associated with central venous catheter sepsis; three episodes of skin cellulitis; one episode of urinary tract infection; one episode of upper respiratory tract infection; and one episode of oral herpes simplex virus infection. Two patients had sinusitis; one episode was fungal. One patient had repeated stool cultures positive for vancomycin-resistant Enterococcus, and one patient had repeated stool cultures positive for Clostridium difficile. One patient had vancomycin-resistant Enterococcus septicemia.
Response
Of 16 assessable CML-BP patients, six (37%) obtained a clinical CR—that is, they returned to chronic-phase disease (Table 5). Three of these six patients received troxacitabine as their first therapy for CML-BP; one patient had disease that failed to respond to STI571 as prior sole therapy for CML-BP. One patient with CML-BP had extensive lytic bone lesions; she was unable to tolerate the procedures necessary to assess response. Although not assessable, she did not clinically respond and ultimately died as a result of progressive disease. None of six patients with ALL displayed a significant response. One patient with refractory MDS (refractory anemia with excess blasts in transformation) was treated on this study; this patient’s disease did not respond to therapy.
Systemic Exposure-Response Relationships The pharmacodynamic relationship between troxacitabine exposure and percentage of patients with toxicity (grade 3 stomatitis, hand-foot syndrome, or both) or oncolytic effect during course 1 of the prior phase I study is provided in Fig 2. No patients with day 5 AUC values in quartile 1 to 3 experienced grade 3 stomatitis or hand-foot syndrome, whereas two (50%) of four of patients with AUC values in quartile 4 experienced grade 3 stomatitis or hand-foot syndrome (one patient treated at the 8.0 mg/m2 dose level experienced grade 3 hand-foot syndrome and one patient treated at 10.0 mg/m2 experienced grade 3 stomatitis). An oncolytic effect was observed in three (75%) of four, three (60%) of five, four (80%) of five, and four (100%) of four patients with AUC values in quartiles 1, 2, 3, and 4, respectively. The Emax model was fitted to the data, and the AUCrange50 associated with an oncolytic effect was 0.55 (SE, 0.24).
Nucleoside analogs, including cytarabine and fludarabine, are active antileukemic agents. Troxacitabine is a novel nucleoside L-enantiomer with significant cytotoxic activity.10,11 Troxacitabine undergoes phosphorylation to its mono-, di-, and triphosphate forms and is incorporated into DNA but not RNA.14 The triphosphate of troxacitabine is a substrate for both replicative and repair DNA polymerases.14 Troxacitabine is a complete DNA chain terminator, probably because the dioxolane ring of its structure lacks the necessary hydroxyl moiety for chain elongation (Fig 1). The cytotoxicity of troxacitabine against some tumor cell lines is directly correlated with the amount of its monophosphate present in DNA terminals.10 Chain excision of integrated troxacitabine monophosphate occurs slowly.15 DNA exonucleases display preference for D- over L-configuration nucleoside analogs at the 3' termini of DNA, making them unlikely candidates as the enzyme responsible for the removal of troxacitabine from DNA.14,16-22 Chou et al15 have identified human apurinic/apyrimidinic DNA endonuclease (APE1), also known as HAP-1 or Ref-1, as the major enzyme that removed troxacitabine monophosphate from DNA within leukemia cells. As with cytarabine, deoxycytidine kinase, which lacks chiral specificity, catalyses the monophosphorylation of troxacitabine.9,10 Deoxycytidine deaminase, however, has more chiral specificity and cannot deaminate troxacitabine to an inactive form. The role of changes over time in the level or function of deoxycytidine kinase and deoxycytidine deaminase in AML blasts as possible mediators of cell resistance to cytarabine has been investigated, but no clear pattern has been described.23-25 Troxacitabine has a unique pattern of cellular uptake and metabolism. Nucleoside-specific membrane transporters (NSMT) mediate plasma membrane permeation of many nucleoside analogs, including cytarabine and fludarabine.26 In human prostate carcinoma DU-145, troxacitabine is transported rapidly into cells by both equilibrative sensitive and insensitive nucleoside transport systems, with subsequent accumulation of troxacitabine monophosphate, diphosphate, and triphosphate in a time- and concentration-dependent manner.26 Gati et al26 have reported that the cellular content NSMT in blasts from patients with AML and ALL correlate with the in vitro sensitivity to cytarabine. Because troxacitabine is not dependent on NSMT to achieve a lethal intracellular concentration, it may thus not be susceptible to NSMT-mediated mechanisms of resistance to cytarabine. The formation of troxacitabine diphosphate increases linearly with increasing extracellular drug concentration, unlike with cytarabine, which lacks proportionality between cytarabine triphosphate formation and extracellular cytarabine concentration with high-dose cytarabine regimens that achieve serum levels of more than 10 µM.27 Troxacitabine does not inhibit ribonucleotide reductase and may thus be mechanistically complementary to several nucleosides that are cytotoxic via ribonucleotide reductase inhibition (eg, (E)-2'-deoxy-(fluoromethylene)cytidine).9 Because troxacitabine may potentially be active in cytarabine–resistant leukemias, we carried out an initial phase I study of troxacitabine in patients with advanced leukemia.13 Because responses on that study were encouraging, we thus expanded that study to conduct the phase II study described here. 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 as a result of deamination. In contrast, troxacitabine has a long terminal half-life (82 hours) and a systemic clearance comparable to the glomerular filtration rate (137 mL/min).13 Consistent with the latter observation, the majority of troxacitabine is 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 on the phase I study in patients with advanced leukemia.13 These concentrations are in the range of those indicated to have growth inhibitory activity in vitro in a variety of human normal and tumor cell lines (5 to 150 nmol/L).
Although the pharmacokinetic studies performed in conjunction with a phase I study13 were not designed to define the therapeutic index for troxacitabine given as a 30-minute infusion daily for 5 consecutive days every 3 to 4 weeks, it is apparent that patients experienced an oncolytic response at levels of systemic exposure below those associated with severe toxicity (Fig 2). In this analysis, we defined oncolytic effect as evidence of hematologic recovery with less than 20% MLI, which is a more demanding requirement that that of previous reports, in which it has been defined as a This phase II study of troxacitabine in patients with advanced leukemia confirmed its antileukemic activity in AML and CML-BP, and better defined the toxicity profile of this agent in this patient population. The dose-limiting toxicities on the phase I leukemia study were stomatitis and hand-foot syndrome; these were also the chief toxicities observed on the currently reported study.13 Other extramedullary toxicities seen on this phase II study included skin rashes that were mild, moderately itchy, not generalized, and resolved completely with rapid recovery from attributable symptoms on a 5-day course of 20 mg daily of orally administered prednisone. Hand-foot syndrome tended to occur in second or subsequent courses of therapy, even when the interval between courses was prolonged. The typical hand-foot syndrome seen was markedly more pronounced in the hands and usually consisted of skin erythema, with periarticular soft tissue swelling associated with a sensation of skin tightness or itchiness, with resolution usually involving some degree of skin peeling. These signs and symptoms typically resolved over the course of a 3- to 5-day period. Patients who developed grade 3 hand-foot syndrome had painful skin blistering and desquamation that caused moderate to severe limitation in hand movements and walking; these signs and symptoms typically resolved over the course of a 5- to 7-day period. We assessed whether any relationship existed between the amount and timing of prior cytarabine exposure and its impact on subsequent troxacitabine toxicities and could not find any evidence for such a relationship. Despite marked improvements in front-line therapy, relapsed adult ALL remains a particularly refractory condition with no effective current therapy.30-32 None of the six heavily pretreated adult patients with ALL on this study responded. Although phase II studies of troxacitabine in patients with refractory multiple myeloma, lymphoma, or chronic lymphocytic leukemia are ongoing, no further single-agent studies of troxacitabine in adult patients with ALL are being planned. Troxacitabine had significant activity in this study group of patients with refractory AML—not in terms of response to a single agent alone, but also in terms of the durability of these responses. Two patients with AML experienced CR; a third experienced PR (Fig 3). These responses to a single-agent nucleoside analog in patients whose disease had failed to respond to prior high-dose cytarabine therapy are of interest. All responses were to the first course of therapy; neither of the patients who experienced CR had experienced relapse at more than 18 and 12 months, respectively. The patient who experienced a PR had disease that failed to respond to four subsequent lines of chemotherapy and died after a matched unrelated SCT. Because CR is rarely seen in leukemia phase I studies, the definition of lesser responses (eg, induction of marrow hypocellularity, significant reduction of marrow or peripheral-blood blasts), likely to predict for CR in patients with less advanced disease, would be of value to protect against too early dismissal of potentially active drugs.
The distinction between primary and secondary resistance refers to whether or not the bone marrow transiently indicated hypocellularity or a more than 50% reduction in bone marrow blasts percentages while on the first course of therapy. This data may allow us—if not in individual studies, then on an aggregate of phase I and phase II studies—to establish whether marrow suppression, even if transient, is in fact indicative of meaningful antitumor activity in leukemia. The analysis summarized in Fig 2 demonstrates that patients experienced an oncolytic response at levels of systemic exposure of troxacitabine below those associated with severe toxicity. Lower doses associated with less stomatitis and hand-foot syndrome may be worthy of exploration as maintenance regimens or as a component of consolidation therapy in responding patients. We are also exploring these lower doses as a component of combination regimens in ongoing phase II studies. These studies are investigating the activity of troxacitabine when given in combinations with idarubicin, cytarabine, topotecan, or gemtuzumab ozogamicin to patients with refractory AML, MDS, or CML-BP. Of 17 patients with CML-BP treated on this study, six returned to a second chronic phase. The durations of second chronic phase in these patients were 6 to 18 or more months. This is an unusually high rate of clinically meaningful response to a single agent. All patients had myeloid blastic-phase phenotype, which is refractory to current therapies. We have previously analyzed the results of therapy in a cohort of 162 adult patients with a diagnosis of myeloid CML-BP treated at the M.D. Anderson Cancer Center between 1986 and 1997.33 Only first salvage therapy was considered for the purpose of this analysis. Ninety patients were treated with intensive chemotherapy, 31 with decitabine and 41 with other single agents, including fazarabine, tallimustine, homoharringtonine, topotecan, and mithramycin.34-39 Thirty-six patients (22%) had an objective response. Response rates were similar among patients treated with intensive chemotherapy (28%) or with decitabine (26%). In aggregate, other single agents displayed objective response rates of 7%. The median duration of remission for all patients was 29 weeks, and the median overall survival 22 weeks. The median survival times were 29 weeks with decitabine, 21 weeks with intensive chemotherapy, and 22 weeks with other agents.
A comparison of survival in the CML-BP cohort treated in the study reported here with that in the previously reported 162 patients is illustrated in Fig 3. Encouraging results with novel bcr-abl tyrosine kinase inhibitors, in terms of hematologic and cytogenetic responses in interferon alfa–resistant patients, have been reported.40 In a phase I study of STI571, patients with interferon alfa–resistant chronic-phase chronic myelogenous leukemia who received
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) or grade 3 or greater nonhematologic toxicity (hand-foot syndrome, stomatitis, or both) (•) after the first course of treatment in a phase I leukemia study.
75% decrease in circulating blasts.
5' exonuclease. Biochem Pharmacol 50: 815-821, 1995
