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Phase I Clinical and Pharmacogenetic Study of Weekly TAS-103 in Patients With Advanced Cancer

From the Committee on Clinical Pharmacology, Section of Pediatric Hematology-Oncology, Department of Pediatrics; Section of Hematology-Oncology, Department of Medicine; Department of Human Genetics and Cancer Research Center, University of Chicago, Chicago, IL; Covance Laboratory, Madison, WI; and ClinTrials Res Inc, Morrisville, NC.

Address reprint requests to Lalitha Iyer, PhD, Department of Medicine and Committee on Clinical Pharmacology, University of Chicago, 5841 South Maryland Ave, MC 2115, Chicago, IL 60637; email: liyer{at}medicine.bsd.uchicago.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: TAS-103 is an inhibitor of both topoiso-merase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103.

PATIENTS AND METHODS: Thirty-two patients were treated with escalating doses (50 to 200 mg/m²) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m² dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques.

RESULTS: DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m² and in 3 of 6 patients at 200 mg/m². At 160 mg/m², there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P < .05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = -0.63, P < .05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103.

CONCLUSION: We recommend a dose of 130 to 160 mg/m², or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN CANCER THERAPEUTICS, anticancer agents that specifically inhibit topoisomerase I, such as camptothecin derivatives (irinotecan and topotecan), or topoisomerase II, such as epipodophyllotoxins, are currently in use for the treatment of a variety of solid and hematologic malignancies. Recently, several compounds have been demonstrated to exhibit dual topoisomerase I and II inhibitory activity. TAS-103, a novel quinoline derivative, is one such compound.¹ In preclinical pharmacology studies involving the use of murine and human tumor cell lines as well as human tumor xenografts, TAS-103 demonstrated broad and potent antitumor activity.^1,2 In addition, it has been demonstrated by the use of various cell lines that the presence of the multidrug resistance–associated proteins P-glycoprotein, multidrug resistance protein, and lung resistance protein do not affect TAS-103 cytotoxicity.³ Toxicity observed in preclinical studies was mainly dose-related myelosuppression. In animal studies, TAS-103 was metabolized mainly to TAS-103-glucuronide (TAS-103-G); other metabolites included demethyl-TAS-103 (DM-TAS-103), which is also active; DM-TAS-103-glucuronide (DM-TAS-103-G); and TAS-103-N-oxide (NO-TAS-103).⁴ Recently, Iyer et al⁵ demonstrated that TAS-103 is glucuronidated to TAS-103-G in vitro, using both human and rat liver microsomes. This reaction was predominantly by UGT1A1, with some metabolism by UGT2 isoform(s).

Glucuronidation results from the activities of a multigene family of UGT enzymes, the members of which exhibit specificity for a variety of endogenous substrates and xenobiotics.^6-8 UGTs are broadly classified into two distinct gene families. UGT1 is further subclassified into multiple isoenzymes, all of which have a conserved carboxyl region encoded by exons 2 to 5, with a variable region encoded by various exons 1. Each isoform of the UGT2 family is a separate gene product, of which at least eight isoenzymes have been identified.^7-9 Several studies have demonstrated that mutations in the coding and promoter regions of UGT1A1 influence conjugation of the enzyme with its natural substrate, bilirubin, thus causing unconjugated hyperbilirubinemias known as Crigler-Najjar type I syndrome and Gilbert’s syndrome, respectively.^10,11

The objectives of our phase I trial were to determine the maximum-tolerated dose (MTD), and dose-limiting toxicity (DLT) of TAS-103 when administered weekly in three doses and to investigate its pharmacokinetics. As a secondary objective, because UGT1A1 enzyme was demonstrated in vitro to be mainly responsible for the metabolism of TAS-103 to its major metabolite, TAS-103-G, we hypothesized that polymorphisms in the promoter region of UGT1A1 gene would determine individual pharmacokinetics of TAS-103 and thus, toxicity in patients.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Eligible patients had pathologically confirmed cancer refractory to standard therapy or for which no standard therapy is known to exist; measurable or assessable disease; adequate performance status (Karnofsky score of > 60%); recovery from toxicity of prior therapy; and willingness to provide informed consent. Patients also had adequate end-organ function, including adequate hepatic function (bilirubin level of 1.6 mg/dL and transaminase elevations of 2.5 x normal levels) and adequate renal function (creatinine of < 1.5 x normal levels). Patients with brain tumors, hematologic malignancies, and patients on therapeutic anticoagulants were excluded from study. Pregnant women were also excluded from study. Informed written consent was obtained from all subjects in accordance with institutional and federal guidelines.

Drug Formulation
TAS-103 was supplied by Taiho Pharmaceutical Co., Ltd. (Tokyo, Japan) in 20-mL vials containing 100 mg of drug as a red-orange to yellow lyophilized sterile powder with 10 mg of polysorbate 80, 0.5 N sodium hydroxide in a quantity sufficient to adjust the pH to 3.0, and nitrogen (United States Pharmacopeia). Vials of lyophilized TAS-103 were dissolved in 20 mL of sterile water for injection. The reconstituted solution was further diluted immediately in physiologic saline to a final concentration of no more than 1 mg/mL (0.1% solution). The final solution is stable at room temperature for 48 hours.

Treatment Protocol
Patients received TAS-103 as a continuous IV infusion over 1 hour. The starting dose was 50 mg/m² because another phase I study with a three-week schedule did not show any toxicities at this dose level.¹² The weekly dose was sequentially doubled up to 200 mg/m², at which level significant toxicity was observed. Thereafter, the dose was reduced by 25% to 160 mg/m² and subsequently to 130 mg/m². At least two patients were treated at each dose level. One dose of TAS-103 was administered weekly for 3 weeks, repeated every 35 days. Patients were evaluated for drug-related toxicities and disease status at the end of each dosing cycle. Those who had progressive disease were withdrawn from study. Complete blood counts and serum chemistries were taken weekly while patients were on study. Toxicities were evaluated in accordance with the National Cancer Institute (NCI) guidelines on grading of common toxicities from antineoplastics. DLT during a treatment cycle was defined as any one of the following occurrences: absolute neutrophil count (ANC) less than 500/µL for more than 72 hours’ duration; grade 4 neutropenia of any duration with fever more than 38.3°C; grade 4 thrombocytopenia (platelets < 25,000/µL); grade 3 or 4 neutropenia or grade 3 thrombocytopenia on a treatment day; grade 3 nonhematologic toxicity excluding grade 3 nausea or vomiting; grade 2 toxicity that was slowly reversible, including neurologic, pulmonary, cardiac toxicities or that exposed the patient to excessive risk or discomfort; any unresolved toxicity resulting in treatment delays of 4 weeks; and any episode or finding that in the clinical judgment of the investigator was considered dose limiting. For patients who received additional treatments after the first TAS-103 cycle, the above toxicity criteria were also adopted but referred to as DLT for repeated dosing.

Pharmacokinetic Study
Pharmacokinetic analysis was conducted in all patients after the first DLT was observed. At the 130-, 160-, and 200-mg/m² dose levels, blood samples (5 mL) for analysis were obtained at the following times: pretreatment; 15 minutes into infusion; at the end of infusion; and at 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after TAS-103 administration. Samples were immediately centrifuged at 2,500 x g for 10 minutes to obtain plasma, which was then stored at -70°C until analysis.

Plasma concentrations of TAS-103 and TAS-103-G were determined by a modified method of that described by Azuma and Urakawa.⁴ Briefly, TAS-103, TAS-103-G, and an internal standard, TAS-1-018, were extracted from human plasma using solid-phase extraction cartridges. A solution of formic acid/acetone/methanol (1:50:50) was used to elute the compounds. The eluent was evaporated to dryness and reconstituted in 0.07% trifluoroacetic acid/acetonitrile (84/16). Separation was achieved by high-performance liquid chromatography (Shimadzu LC-10AS, Kyoto, Japan) on a reverse-phase analytic column (J’sphere ODS-L80, 150 x 4.6 mm, 4-µm particle size; YMC, Kyoto, Japan) with a mobile phase gradient of acetonitrile and 0.07% trifluoroacetic acid, varying the acetonitrile concentration from 16% to 34%. Visible detection of TAS-103 and TAS-103-G was performed at 460 nm using a variable wavelength detector (SPD-10AV, Shimadzu). The minimum levels of quantification for TAS-103 and TAS-103-G were 5 and 10 ng/mL respectively. The observed coefficient of variation between days for the standard curves was less than 10%.

UGT1A1 Genotyping Assay
During our phase I trial, findings of the in vitro glucuronidation studies in liver microsomes were published by Iyer et al;⁵ as a result, we amended our protocol to include UGT1A1 genotyping of patients. Only those patients who gave prospective consent for donation of germline DNA and genotyping were included in this portion of the study. DNA was extracted from 3 mL of peripheral blood by the process of cell lysis, followed by RNAse treatment, removal of protein, and DNA precipitation using the Puregene DNA extraction kit (Gentra Systems, Minneapolis, MN). Approximately 40 ng of DNA was subject to amplification by polymerase chain reaction. The amplification primers used have been described elsewhere,¹³ where the sequence of the forward primer is 5'-GTCACGTGACACAGTCAAAC-3' and that of the reverse primer is 5'-TTTGCTCCTGCCAGAGGTT-3'. These primers flank the polymorphic TA locus in the promoter region of the UGT1A1 gene and amplify a 98-bp fragment when a (TA)₆TAA allele is present and a 100-bp fragment when a (TA)₇TAA allele is present. The reverse primer was labeled with a fluorescent dye at its 5'-end to permit visualization of the amplification product. The amplification reactions were performed in a 10-µL volume mixture consisting of 1.5 mmol/L of MgCl₂, 250 µmol/L of dNTPs, 0.8 µmol/L of each primer, and 0.5 U of Taq polymerase (Amplitaq Gold, Perkin-Elmer, San Francisco, CA). DNA was amplified in a Perkin-Elmer model 9600 thermocycler for 35 cycles at 95°C for 30 seconds, 55°C for 30 seconds, and 72°C for 30 seconds, followed by a final extension at 72°C for 10 minutes. Control DNAs from individuals known to have a 6/6, 6/7, and 7/7 genotype were included in the PCR analysis.

PCR fragments were subjected to gel electrophoresis on an ABI 377 DNA analyzer (Perkin-Elmer). Amplified products were diluted in a formamide and dextran blue loading buffer, combined with size standard (GS-350, Perkin Elmer), denatured at 95°C, and loaded onto a 6% denaturing polyacrylamide gel. Electrophoresis was performed for 3.5 hours as per the manufacturer’s recommendations. Fragments were sized using the Genescan and Genotyper softwares (Perkin-Elmer). Genotypes were assigned as 6/6, 6/7, and 7/7 for patients homozygous for allele 6, heterozygous for allele 7, and homozygous for allele 7, respectively.

Data Analysis
The pharmacokinetics of TAS-103 and TAS-103-G were analyzed using noncompartmental methods with WinNonlin (PharSight, Corp, Apex, NC). The terminal elimination half-life (t_1/2) of TAS-103 was estimated from the slope of the terminal concentrations of the log concentration–time curve for each patient. The area under the concentration–time curve for the study period, AUC_last, for TAS-103 and TAS-103-G was estimated by linear-log trapezoidal technique. The AUC to infinity (AUC_0-) was calculated by the following relationship: AUC_0- = AUC_last + C_last/_term, where _term (terminal elimination rate constant) is the absolute value of the slope of the terminal log-linear phase and C_last is the last quantifiable concentration. The time points used to derive _term were chosen after visual inspection of the log concentration–time curves of individual patients. When C_last was below the limit of quantitation (LOQ), a concentration of TAS-103 (2.5 ng/mL) or TAS-103-G (5 ng/mL) equivalent to 50% of the LOQ was assumed as C_last. Clearance (CL) of TAS-103 was calculated as the ratio of dose to AUC_0-. Pharmacokinetic parameters for each patient were estimated, and the mean was derived.

Complete blood cell counts and blood chemistry studies were performed in all patients on a weekly basis. Patients did not receive the day 15 dose (third dose) of TAS-103 if absolute neutrophil count (ANC) was less than 1,000/µL. As such, we adopted ANC on day 15 of study as our pharmacodynamic end point to correlate with TAS-103 pharmacokinetics. Patient body-surface area (BSA) was correlated with clearance of TAS-103. The UGT1A1 genotypes of patients were also related to AUCs of TAS-103 and TAS-103-G and to TAS-103 clearance.

Statistical Analysis
Pearson’s test was used to evaluate relationships between AUC data for TAS-103 and TAS-103-G, TAS-103 exposure and ANC nadir, and BSA and TAS-103 clearance. Differences between TAS-103 total systemic clearance at the various dose levels were evaluated using Kruskal-Wallis statistics, and P .05 was considered statistically significant.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Demographics
A total of 32 patients were enrolled in the study. The characteristics of the patients are listed in Table 1. Of the nine patients enrolled at the 200-mg/m² dose level, only six were assessable ( Table 2). The other three patients did not complete the first cycle of treatment because of progressive disease while on study.

Pharmacokinetics
The mean plasma concentration–time profiles of TAS-103 and its major metabolite, TAS-103-G, after i.v. administration of 130, 160, and 200 mg/m² doses of TAS-103 are shown in Fig 1. As depicted, TAS-103 exhibits multicompartmental pharmacokinetics and is detectable in plasma up to 24 hours after infusion. The mean (± SD) estimated pharmacokinetic parameters are listed in Table 3. The estimated mean terminal half-life at the doses studied was 3.9 (± 1.9 hours), with a range of 2.8 to 5.9 hours. Clearance of TAS-103 appeared to be independent of dose. However, the AUC of TAS-103-G appears to increase disproportionately with dose. There is a significant linear relationship between AUCs of TAS-103 and TAS-103-G (r = 0.76, P = .004), as depicted in Fig 2. There was no significant relationship between BSA and clearance of TAS-103 (r = 0.34, P = .54).

View larger version (12K): [in this window] [in a new window]   Fig 1. Mean profile of plasma TAS-103 and TAS-103-G concentrations after administration of TAS-103. Plasma concentrations of TAS-103 ( and TAS-103-G (•) were determined at various time points. Zero time point refers to start of infusion.

View larger version (14K): [in this window] [in a new window]   Fig 2. Plot of relationship between AUC of TAS-103 versus AUC of TAS-103-G and UGT1A1 genotypes of patients treated at the 160-mg/m2 dose level.

View larger version (9K): [in this window] [in a new window]   Fig 3. Scatterplot of AUC of TAS-103 versus day 15 ANC in patients treated at the 160-mg/m2 dose level. Plot A represents data of all patients, and plot B represents data of all patients, excluding the data point highlighted on plot A.

View larger version (10K): [in this window] [in a new window]   Fig 4. Scatterplot of UGT1A1 genotypes of patients versus clearance of TAS-103 in patients treated at the 160-mg/m2 dose level.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

In deciding on a therapeutic dosing strategy for a cytotoxic anticancer agent, the relationship between drug exposure and toxicity is usually a key factor to consider. We were disappointed, therefore, that there was only a weak relationship between total TAS-103 pharmacokinetics (AUC) and toxicity (day 15 ANC) for all patients at the 160-mg/m² dose level (Fig 3A), albeit strengthened by the exclusion of an apparent outlier patient from the analysis (Fig 3B). Thus it is conceivable that other factors we have not considered, including interindividual variability in the percentage and disposition of free drug, and/or an active metabolite, such as demethyl-TAS-103, might also influence drug-related toxicity. To assess this possibility, future studies should consider quantitation of demethyl-TAS-103, its glucuronides, and/or the free fraction of TAS-103 because TAS-103 is known to be highly protein bound.¹⁴

It is often desirable to individualize chemotherapy in patients with cancer in order to improve treatment outcome. However, an individualized dosing strategy will be more successful when factors that are mainly responsible for both intra- and interindividual pharmacokinetic variability, and hence toxicity, are minimized. Currently, in the development of anticancer drugs, the MTD of a cytotoxic agent is usually defined without regard to the individual characteristics of the patients. It usually refers to the dose for which unacceptable toxicity attributable to a cytotoxic agent is observed in a predefined proportion of patients, enrolled on a particular schedule. Using this model, it is conceivable that patients who are predisposed by genetic variation to toxicity from a drug might experience significant toxicities at dose levels considered subtherapeutic for other patients. For example, UGT enzymes are known to be involved in the biotransformation of several anticancer drugs, and earlier studies have shown that there is a relationship between the DLT of irinotecan (CPT-11) and the glucuronidation of its active metabolite, SN-38.¹⁵ Given the same dose, cancer patients with the (TA)₇TAA polymorphism in the promoter region of UGT1A1 gene have been shown to experience more severe toxicities (ie, diarrhea and neutropenia) from CPT-11 because of decreased glucuronidation of an active metabolite, SN-38 to SN-38G.¹⁶ UGT1A1 enzyme was demonstrated in vitro to be predominantly responsible for the glucuronidation of TAS-103 to TAS-103-G.⁴ In this phase I trial, DLT was observed in all patients with genotype 7/7, compared with fewer numbers of patients with genotypes 6/7 and 6/6. Because there is no obvious relationship between UGT1A1 genotype and pharmacokinetics, this may be of no significance.

In this study, we have investigated the influence of the (TA)₇TAA polymorphism in the promoter region of UGT1A1 on pharmacokinetics and toxicity of TAS-103. This polymorphism has been shown to be involved in the etiology of Gilbert’s syndrome,^13,17 which is manifested as a mild hyperbilirubinemia and is quite common in Caucasian populations (15% to 20%).¹³ This polymorphism results in reduced expression levels of UGT1A1 protein.¹⁷ Recently, there have been reports of polymorphisms in the coding region of UGT1A1 that also result in mild hyperbilirubinemia. These polymorphisms (Gly71Arg, Pro229Gln, Pro364Leu, Tyr486Tyr) have been found at a high frequency (30%) only in Asian populations so far.^18,19 There were no patients of Asian origin among our patients who underwent genotyping, and hence, screening for coding region polymorphisms was not performed. Given the small number of patients in this study and the fact that we have only performed a partial analysis of genetic alterations of UGT1A1 in our patients, we cannot make any conclusions regarding the relationship between polymorphisms in UGT1A1 gene and TAS-103 disposition or toxicity. However, because more patients with polymorphisms in the promoter region of UGT1A1 seem to experience TAS-103 drug-related toxicity, future studies involving more patients and other known coding-region mutations in UGT1A1 in specific ethnic groups are warranted.

To the best of our knowledge, this is the first study attempting to use pharmacogenetics as a tool in the early stages of development of an anticancer agent. This approach potentially provides a unique opportunity to clearly define optimal doses of an antineoplastic agent and minimize treatment-related toxicities in later studies. In this study, it might have been possible to define a better relationship between genotype and toxicity of TAS-103 if we had instituted the UGT1A1 genotype component of the study early, especially in patients who received the 200-mg/m² doses. We will suggest that future clinical studies involving anticancer agents, including TAS-103, that are mainly metabolized in humans by glucuronidation should also include genotyping of patients because this attribute promises to be a key factor in determining the extent of drug clearance, toxicity, or efficacy of such drugs.

	ACKNOWLEDGMENTS

 
Supported by Taiho Pharmaceutical Co. Ltd., Tokyo, Japan.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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15. Gupta E, Lestingi TM, Mick R, et al: Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhea. Cancer Res 54: 3723-3725, 1994[Abstract/Free Full Text]

16. Iyer L, Janisch L, Das S, et al: UGT1A1 promoter genotype correlates with pharmacokinetics of irinotecan (CPT-11). Proc Am Soc Clin Oncol 19: 178a, 2000 (abstr 690)

17. Bosma PJ, Roy Chowdhury J, Bakker C, et al: The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 333: 1171-1175, 1995[Abstract/Free Full Text]

18. Akaba K, Kimura T, Sasaki A, et al: Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: A common missense mutation among Japanese, Koreans and Chinese. Biochem Mol Biol Int 46: 21-26, 1998[Medline]

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Submitted April 25, 2000; accepted December 13, 2000.

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