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© 2002 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of Novel L-Nucleoside Analog Troxacitabine Given as a 30-Minute Infusion Every 21 DaysByFrom the Centre Hospitalier de l’Universite de Montreal, Montreal; Princess Margaret Hospital, Toronto; National Cancer Institute of Canada, Clinical Trials Group, Queen’s University, Kingston; and BioChem Pharma Inc, Laval, Canada; and Cancer Therapy and Research Center, San Antonio, TX. Address reprint requests to Dr Karl Belanger, CHUM, Hôpital Notre-Dame, 1560, Sherbrooke St East, Montreal, Quebec, Canada H2L 4M1; email: Karl.belanger.chum{at}ssss.gouv.qc.co
PURPOSE: Troxacitabine (Troxatyl, BCH-4556; BioChem Pharma Inc, Basingstoke, United Kingdom) is a novel synthetic L-nucleoside analog with activity against a broad range of human tumors in preclinical models. Preclinical toxicity suggested a predictable toxicity profile consistent with an agent of this class, with evidence of interspecies differences. We conducted a phase I study of troxacitabine given as a 30-minute infusion once every 21 days. PATIENTS AND METHODS: The starting dose of troxacitabine was 0.025 mg/m2, based on toxicology data from the most sensitive species studied (cynomolgus monkey). Doses were doubled until grade 1 skin or mucosal or grade 2 other toxicity was encountered. A modified Fibonacci scale was used. RESULTS: A total of 45 patients were enrolled at 13 dose levels. Most common nonhematologic side effects were skin rash (44%), lethargy (29%), nausea (24%), alopecia, dry skin (18%), anorexia (13%), neurosensory symptoms (13%), and hand-foot syndrome (13%). In patients treated with prednisone 25 mg/d orally for 5 days, starting on day 1, skin rash was less problematic. Two patients at 12.5 mg/m2 experienced dose-limiting (grade 4) granulocytopenia. Confirmed partial responses were documented in one patient with previously untreated renal cell carcinoma with metastatic lung and bone lesions and in one patient with an unknown primary tumor. Eighteen patients had a best response of stable disease with a median duration of 5.1 months (range, 2.1 to 18.7 months). CONCLUSION: When given in this schedule, the maximum-tolerated dose of troxacitabine is 12.5 mg/m2, and the recommended dose for additional phase II studies is 10 mg/m2 once every 21 days with steroid premedication.
TROXACITABINE (BCH-4556, Troxatyl; BioChem Pharma Inc, Basingstoke, United Kingdom) is a novel synthetic L-nucleoside analog (Fig 1) that was initially designed for antiretroviral therapy. In vitro screening assays studies revealed that it causes cytotoxicity, which led to the evaluation of this molecule as a cytotoxic agent in neoplastic diseases. In vitro and in vivo (including human tumor xenograft model) studies demonstrated that troxacitabine has activity against a broad range of human tumors, including drug-refractory tumors that overexpress MDR.1,2 The best responses were obtained in renal and prostate cancer cell lines and MDR-positive human leukemia cell line HL-60-R10, although the responses were dose and schedule dependent.3-5 Tumor responses and increased tumor-free survival were also noted from xenograft experiments of colon adenocarcinomas and head and neck tumors.
Many possible mechanisms of action of troxacitabine have been reported. Troxacitabine undergoes phosphorylation to its monophosphate, diphosphate, and triphosphate forms and is incorporated into DNA. This molecular event is thought to be the principal cytotoxic mechanism. In vitro, the triphosphate form of troxacitabine is a substrate for DNA polymerases and is a potent inhibitor of their function.6 Furthermore, evidence indicates that troxacitabine is a complete chain terminator. Moreover, in comparison with other nucleoside analogs, such as cytarabine (ARA-C), the intracellular accumulation of phosphorylated molecules of troxacitabine is proportional to its extracellular concentration, with prolonged retention of the phosphorylated metabolites. The major route of troxacitabine cellular uptake is passive diffusion. Deficiencies in nucleoside transporters that render tumor cells resistant to ARA-C do not significantly affect troxacitabine cytotoxicity.7 The elimination of triphosphated troxacitabine also differs from ARA-C, because it is slow and biphasic, with intracellular half-lives of 3.5 hours and longer than 20 hours, respectively, for each phase.8 These results suggest that troxacitabine might be efficacious with treatment regimens of either infrequent higher doses or daily repeated lower doses. The toxicity of troxacitabine was evaluated with different doses and modes of administration both in rats and cynomolgus monkeys. Rats were generally tolerant to large single doses or consecutive daily doses of troxacitabine. A single dose of 12,000 mg/m2 did not produce any detectable side effect. With consecutive daily doses, toxicity was mainly hematological, with decreased white counts and red cell parameters. Gonadal toxicity was also documented by spermatocyte depletion and testicular atrophy. Cynomolgus monkeys were more sensitive, with mild hematological toxicity at 12 mg/m2 administered as a single dose considered the toxic dose low (TDL). Mortality and constitutional effects were observed at slightly more elevated doses (36 mg/m2). Data on consecutive doses demonstrated severe toxicity with mortality, severe myelosuppression, mucositis, and hepatic toxicity. The pharmacokinetics of troxacitabine after intravenous administration were examined in rats and monkeys. Troxacitabine exhibited dose-proportional increases in exposure (Cmax and area under the curve [AUC]) in both species. However, exposure in monkeys was higher than in rats at any given dose when compared on a milligram/kilogram basis. These species differences may be the result of a slower clearance rate in monkeys (0.50 to 0.78 L/kg/h) versus rats (1.04 to 1.18 L/kg/h), resulting in a slightly longer half-life in monkeys (0.36 to 0.55 hours) relative to rats (0.29 to 0.34 hours). Because of interspecies variability in toxicity and pharmacokinetic profiles between rats and monkeys, comparative myelosuppression studies were performed using both monkeys and human progenitor cells.9 These studies suggested that human progenitor cells may be up to 50-fold more sensitive to troxacitabine than cynomolgus monkey progenitor cells, principally after 1 hour of exposure. The effect was less pronounced for continuous exposure. Because of the evidence of interspecies differences in toxicity as well as the apparent sensitivity of humans compared with monkeys, it was estimated that drug toxicity for humans could be expected at or above 0.2 mg/m2, assuming the same factor of variability as the myelotoxicity assay. Based on these data, various schemes of administration were tested in humans. This study reports the results of a phase I and pharmacokinetic study of troxacitabine administered as a single dose every 21 days. Myelosuppression being a potential dose-limiting toxicity, it was decided to start the first level at a conservative starting level dose of 0.025 mg/m2, which represents 1/150th of the TDL in cynomolgus monkeys. It was also decided to treat only one patient per level for the first two levels only because the accepted starting dose was low and unlikely to cause significant side-effects.
Patient Population Patients with histologically documented advanced or metastatic solid tumors refractory to standard curative therapy or for which no standard therapy of proven benefit existed were eligible for the study. They must have had clinically or radiologically assessable disease. Previous radiotherapy and one prior systemic chemotherapy for metastatic disease were allowed as long as the last treatment was at least 3 weeks before study entry and any resulting toxicities had resolved. Patients had to have acceptable bone marrow (granulocyte count  1.5 109/L; platelet count 125 x 109/L), liver (serum bilirubin level  upper normal limit; AST 3 x upper normal limit), coagulation (prothrombin time normal; partial thromboplastin time normal), and kidney function (serum creatinine level upper normal limit or measured creatinine clearance 60 mL/min), and a Eastern Cooperative Oncology Group performance status 2. Patients were excluded if they suffered from an uncontrolled medical conditions, an active serious infection, CNS metastasis, or had prior exposure to investigational phase I anticancer agents or clinically detectable third space fluid collection. Pregnant or lactating women were ineligible; men and women of childbearing potential must have agreed to adequate contraception for the duration of the study. The medical ethics committee of each center participating in the study, Centre Hospitalier de l’Universite de Montreal, and Princess Margaret Hospital approved the study protocol, and all patients gave written informed consent.
Study Design
Drug Supply and Administration Initially, no routine premedication was given. If nausea or vomiting was observed, antiemetics were used as needed and were given prophylactically in subsequent cycles. The protocol was amended at dose level 12 (10 mg/m2) to add premedication with prednisone (25 mg orally for 5 days beginning on day 1 before troxacitabine infusion) to all subsequent patients for cycle 1 in an attempt to reduce the incidence and severity of skin rash. Cycles were repeated once every 3 weeks unless there was evidence of disease progression. Doses were reduced for hematologic and other toxicities.
Patient Evaluation Tumor measurements were performed during every other cycle, although response was not a primary study end point. Response was assessed according to NCIC CTG standard criteria. Complete remission was defined as disappearance of clinical and radiological evidence of active tumor, determined by two observations not less than 4 weeks apart; partial remission was defined as a 50% or greater decrease in the overall sum of measured lesions, determined by two observations not less than 4 weeks apart with no simultaneous increase in the size of any lesion or appearance of new lesions; and stable disease was defined as response not fulfilling the criteria for partial remission and not fulfilling the criteria for progressive disease for at least 6 weeks. Progressive disease was defined as an unequivocal increase of at least 25% in the overall sum of measurable lesions or the appearance of new lesions. The response duration was measured from the time measurement criteria were first met until disease progression; stable disease duration was measured from the time of start of therapy until disease progression.
Pharmacokinetics On day 1 of cycle 1, urine was collected continuously from 0 to 24 hours. At the 6.4-mg/m2 dose level, the protocol was amended and urine was collected during the following collection intervals: 0 to 4, 4 to 8, 8 to 12, and 24 to 48 hours after infusion. For each collection interval, the total volume of urine was recorded, and a 20-mL aliquot was frozen at -20°C until analysis. Analytic assay. A validated analytic assay consisting of high-performance liquid chromatography and mass spectrometric detection was used in the analysis of plasma and urine samples. The lower limits of quantitation of troxacitabine in plasma and urine were 0.6 and 10 ng/mL, respectively.
Pharmacokinetic and statistical analysis.
Troxacitabine pharmacokinetic parameters were calculated by standard noncompartmental methods using the program WinNonlin version 2.0 (SCI, Apex, NC). AUC from time 0 to the time of final quantifiable sample (AUCtf) was calculated using the linear trapezoidal method. The AUC was extrapolated to infinity (AUCinf) by dividing the last measured concentration by the terminal rate constant, Relationships between troxacitabine systemic exposure and toxicity during course 1 were explored. Parameters of troxacitabine exposure included total dose (mg), body surface area normalized dose (mg/m2), Cmax, and AUC. Relevant parameters of troxacitabine toxicity included percentage decrements in absolute neutrophil count (ANC) and NCI grade of neutropenia. The relationship between troxacitabine exposure and percentage decrements in ANC were described using a simple maximum effect (Emax) model of drug effect, where the Emax was fixed at 100% and Exposure50 is the exposure at which the effect is 50% of the maximal effect.11 This model was fitted to the data using nonlinear least-squares regression using WinNonlin version 2.0. Pharmacokinetic parameters were described using descriptive statistics. Univariate correlation analysis was used to assess the relationship between estimated creatinine clearance and troxacitabine clearance, body size (body surface area and weight) and troxacitabine clearance, and body size and troxacitabine Vss. Creatinine clearance was estimated using the method of Cockcroft and Gault.11 Univariate correlation analysis of variance was used to assess relationships between troxacitabine dose and pharmacokinetic parameters (eg, clearance) and troxacitabine exposure and grade of neutropenia. If a significant difference was detected by analysis of variance, Tukey’s multiple range test was used to determine which groups differed. The a priori level of significance was set at 0.05.
Patients and Treatment A total of 45 patients (32 males and 13 females) were enrolled onto the study. Patient characteristics are listed in Table 1. At study entry, median age of patients was 52 years (range, 32 to 75 years) and the median Eastern Cooperative Oncology Group performance status was 1 (range, 0 to 2). The 45 patients were registered at 13 dose levels. Starting dose was 0.025 mg/m2, and the MTD was reached at 12.5 mg/m2 (Table 2).
Forty-five patients were assessable for toxicity (Tables 3 and 4). Overall, the most common nonhematologic side-effects thought to be at least possibly related to protocol therapy include skin rash (44% of patients), lethargy (29%), nausea (24%), alopecia and dry skin (18%), anorexia (13%), neurosensory symptoms (13%), and hand-foot syndrome (13%). Forty-four percent of patients had skin rash thought to be related to protocol therapy. Four patients had grade 3 rash; this was felt to be related to protocol in three. At dose level 12 (10 mg/m2), skin rash appeared more frequently and with greater severity (four patients with at least grade 2). The level was expanded and the protocol was amended to add premedication with prednisone 25 mg/d orally for 5 days beginning on day 1 (first dose before troxacitabine infusion) to all subsequent patients for cycle 1 in an attempt to prevent or lessen the incidence and severity of skin rash. In the patients treated with steroid premedication (cycle 1), skin rash was less problematic, with no grade 3 rash reported and no rash at the last level. Hand-foot syndrome was documented in six (13%) patients at the two higher levels (10 and 12.5 mg/m2). This was grade 2 in four patients and grade 3 in two patients. One of the six patients was subsequently rechallenged with recurrence of grade 3 hand-foot syndrome and was ultimately withdrawn because of disease progression. In phase II studies, the initial cohort of patients was treated without prophylactic steroids, and the incidence of rash was felt to be unacceptably high; when prophylactic steroids were used, the incidence was much lower.
Myelosuppression became more common with increasing dose levels, with no grade 3 to 4 hematologic toxicity before the 1.6-mg/m2 dose level and only occasional patients experiencing significant granulocytopenia before the 10-mg/m2 dose level (Table 4). Two patients at 12.5 mg/m2 experienced dose-limiting (grade 4) granulocytopenia. In general, biochemical changes were not considered drug related (Table 5). There were no serious adverse events thought to be related to protocol therapy. One patient died on day 13 of his first cycle; death was likely attributable to an unrelated pulmonary embolus.
Forty-two patients are assessable for response. Disease was not reassessed in two patients, and one patient died of a pulmonary embolus on day 13 of the first cycle. Two confirmed partial responses were documented in a patient with biopsy-proven renal cell carcinoma (no prior chemotherapy) with lung and bone metastases and in a patient with an adenocarcinoma of unknown origin (no prior chemotherapy) with a single cervical lymph node. Interestingly, the patient with renal cell carcinoma also developed hand-foot syndrome and had chemotherapy discontinued but was subsequently rechallenged and achieved a second partial response. Median duration of response was 3.9 months. Eighteen patients had a best response of stable disease with a median duration of 5.1 months (range, 2.1 to 18.7 months).
Pharmacokinetics
Mean plasma concentration time profiles and pharmacokinetic parameters for each dose level are listed in Table 6. Mean Cmax and AUC values increased with increasing troxacitabine dose (Figs 2 and 3; Table 6). Troxacitabine pharmacokinetic parameters were dose independent and characterized by mean ± SD values for t1/2, Vss, and Cls of 13 ± 11 hours, 66 ± 45 L, and 165 ± 66 mL/min, respectively. Approximately two-fold interpatient variability was observed in AUC values. At the higher dose levels (
Urinary recovery of troxacitabine. Urine sampling was performed in 42 patients. Pharmacokinetic data were assessable in 32 patients and were not considered assessable in 10 patients because of incomplete urine collections. An average of 60% of an administered troxacitabine dose was excreted as unchanged drug in the urine during the first 24 hours after treatment (Table 6). An additional 5% of troxacitabine was excreted between 24 to 48 hours. Most troxacitabine (47%) was excreted from time 0 to 4 hours after treatment. A linear correlation was observed between estimated creatinine clearance and troxacitabine systemic clearance (r2 = .269, P = .0007) and renal clearance (r2 = .460, P < .0001). Relationship between troxacitabine pharmacokinetics and toxicity. Data from 41 patients receiving troxacitabine 0.025 to 12.5 mg/m2 were available for clinical pharmacodynamic assessments. AUC was most predictive of the percentage decrements in the ANC using the simple Emax model (AUC50 = 891 ng·h/mL, r2 = .6036) (Fig 4). The mean AUC value was higher (2,283 ng·h/mL) in patients who experienced grades 3 and 4 neutropenia (N = 4) than in those who experienced grade 0 (mean AUC, 577 ng·h/mL) or grades 1 to 2 (mean AUC, 1,525 ng·h/mL) neutropenia. This trend was evident in a subset of patients treated at the two highest dose levels (10 and 12.5 mg/m2), in which patients who experienced grade 3 or 4 neutropenia had AUC values higher than 2,200 ng·h/mL and those with less severe neutropenia had AUC values less than 2,220 ng·h/mL. Dose and Cmax seemed to be less predictive of the severity of neutropenia than AUC.
Troxacitabine is a novel synthetic L-nucleoside analog with several distinct pharmacologic characteristics. It has activity against a broad range of human tumors in preclinical in vitro and in vivo studies. It is a complete DNA chain terminator and is neither transported via the nucleoside transporters nor inactivated by human cytidine deaminase. Sixty percent is excreted unchanged in the urine, and systemic clearance is lower (165 mL/min) and elimination half-life is longer (13 hours) than seen with other nucleoside analogs. These characteristics make the compound particularly interesting to study. The most common nonhematologic side-effect observed was skin rash, which was ameliorated with the introduction of a short course of prophylactic steroids. Granulocytopenia was the dose-limiting toxicity when prophylactic steroids were used and was proportional to the AUC. When given on a 3-week schedule, the maximum-tolerated dose of troxacitabine is 12.5 mg/m2, and the recommended dose for additional phase II studies in solid tumors is 10 mg/m2. In this phase I study, troxacitabine has shown promising antitumor activity, with several patients achieving stable disease and two confirmed partial responses. A second phase I study investigating troxacitabine administered as a 30-minute infusion given weekly for 3 weeks every 4 weeks in solid tumors concluded that the recommended dose for this regimen was 3.2 mg/m2/wk. The dose-limiting toxicity was prolonged myelosuppression. In a third study where troxacitabine was administered as a 30-minute infusion for 5 days every 3 to 4 weeks, neutropenia and skin rash were the dose-limiting toxicities. Neutropenia generally required more than 3 weeks for complete recovery; thus, the dosing interval was increased to 4 weeks. The recommended dose for this regimen is 1.2 mg/m2/d for heavily pretreated patients and 1.5 mg/m2/d for lightly pretreated patients. A response was reported in one patient with metastatic melanoma; 18 patients had a best response of stable disease.12 A phase I study was also completed in patients with refractory acute leukemia. In this study, the recommended dose 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 and hand-foot syndrome in the other. Three complete remissions and one partial remission were observed in 30 assessable patients with acute myeloid leukemia.13 The toxicity profile was similar in all of the phase I studies, and the dose intensity seemed similar across the schedules. Based on the convenience and clinical activity seen with the 3-week regimen, phase II studies were initiated with that schedule in a range of tumor types, including two studies being conducted at the NCIC CTG (NCIC CTG IND.119), a phase II study of troxacitabine in patients with renal cell cancer (and no prior cytotoxic therapy), and NCIC CTG IND.120, a phase II study in patients with stage IIIB or IV non–small-cell lung cancer (and no prior cytotoxic therapy).
We thank Biochem Pharma Inc, Basingstoke, United Kingdom, for the support of this study.
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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
z, which was determined from the slope of the terminal phase of the plasma concentration time curve. A weighting factor of 1/concentration2 was used. The terminal half-life (t1/2) was calculated as 0.693 divided by 
