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© 2003 American Society for Clinical Oncology Use of Positron Emission Tomography in Pharmacokinetic Studies to Investigate Therapeutic Advantage in a Phase I Study of 120-Hour Intravenous Infusion XR5000From the CRC Department of Medical Oncology, Beatson Oncology Centre, Glasgow; and CRC PET Oncology Group, Division of Cancer Medicine, Imperial College School of Medicine, MRC Cyclotron Unit, Hammersmith Hospital, London, UK. Address reprint requests to A.L. Harris, Cancer Research UK Medical Oncology Unit, University of Oxford, Churchill Hospital, Headington, Oxford, OX3 7LJ, UK; email: a.harris{at}icrf.icnet.uk.
Purpose: XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) is a topoisomerase I and II inhibitor. Because the cytotoxicity of XR5000 increases markedly with prolonged exposure, we performed a phase I study of weekly XR5000 by 120-hour continuous infusion over 3 weeks. Patients and Methods: Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m2/120 hrs) for a total of 67 cycles. Three patients underwent positron emission tomography (PET) studies at the maximum-tolerated dose (MTD) to evaluate normal tissue and tumor carbon-11 radiolabeled XR5000 ([11C]XR5000) pharmacokinetics. Results: The dose-limiting toxicity was National Cancer Institute Common Toxicity Criteria (version 1) grade 4 chest and abdominal pain affecting the single patient receiving 4,060 mg/m2/120 hours, and the MTD was 3,010 mg/m2/120 hours. Other grade 3–4 toxicities, affecting single patients at the MTD, were myelosuppression (grade 4), raised bilirubin, vomiting, and somnolence (all grade 3). There was one partial response (adenocarcinoma of unknown primary); the remainder had progressive disease. [11C]XR5000 distributed well into the three tumors studied by PET. Tumor uptake (maximum concentration or area under the concentration versus time curve [AUC]) was less than in normal tissue in which the tumors were located. Tumor exposure (AUC; mean ± SD in m2/mL/sec) increased when [11C]XR5000 was administered during an infusion of XR5000 (0.403 ± 0.1), compared with [11C]XR5000 given alone (0.292 ± 0.1; P < .05), indicating that tumor drug exposure was not saturated. Conclusion: The recommended dose for XR5000 in phase II studies is 3,010 mg/m2/120 hours. PET studies with 11C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.
THE AMSACRINE derivative XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide; NSC 601316), formerly known as DACA, is a DNA intercalator that acts as an inhibitor of both topoisomerase I and II.1,2 It is undergoing clinical assessment because of several potent properties. XR5000 circumvents transport-mediated multidrug resistance caused both by P-glycoprotein and multidrug resistance protein (MRP1).3 In addition, through other mechanisms, it is able to circumvent topoisomerase II inhibitor resistance.4 These properties contrast with other topoisomerase II poisons in clinical use. Accordingly, it has a different cytotoxic profile against tumor cell lines compared with other topoisomerase II inhibitors.4 The effects of XR5000 on topoisomerase I1,2 may account for its ability to overcome topoisomerase II resistance. Dual inhibition of topoisomerase I and II is of potential benefit, because topoisomerase II resistance can confer reciprocal sensitivity to topoisomerase I poisons and vice versa.5 XR5000 has potent activity against a range of epithelial tumor cell lines, but less activity against leukemia lines. The mean 50% inhibitory concentration (IC50) of XR5000 against the National Cancer Institute 60-tumor panel cell line is 2.1 µM (range, 0.42 to 5.4 µM).4 It has curative activity against Lewis lung carcinoma.6,7 Other properties indicate that XR5000 merits clinical investigation. It is lipophilic,7 stable, and soluble in aqueous solution;8 crosses the blood-brain barrier;9 and has good tumor uptake.10 In preclinical models, the main toxicity of XR5000 was neurotoxicity, including agitation and sedation.11 The above properties prompted two clinical trials. In one, XR5000 was given as a 3-hour intravenous infusion on 3 successive days, repeated every 3 weeks.12 In the other trial, XR5000 was given as a single 3-hour infusion regimen, repeated once a week for 3 weeks.13 The maximum tolerated daily doses (MTDs) were 800 and 750 mg/m2, respectively. The dose-limiting toxicity (DLT) in both trials was infusional arm pain. One patient, given XR5000 through a central venous catheter, experienced chest pain with transient electrocardiographic changes but no evidence of myocardial infarction.12 Other toxicities that were dose related were facial flushing; pain and paraesthesia around the mouth, eyes, and nose; lacrimation; somnolence; and agitation. These toxicities were rapidly reversible on treatment discontinuation. Side effects such as nausea and vomiting, myelosuppression, stomatitis, and alopecia were uncommon. XR5000 pharmacokinetics were linear in the previous phase I studies, with estimated values for the protein-free fraction of 0.9% to 3.3%, lower than those in mice and rats—15% and 16%, respectively.14 If values of free-drug area under the concentration versus time curve (AUC) are accurate in interspecies predictions, the effective dose in humans should be approximately 3,000 mg/m2,15 indicating that therapeutic levels were not attained.
The DLT of the initial phase I studies, infusional arm pain, was related to the mode of administration. It was postulated that prolonged infusion of XR5000 by central venous catheter could circumvent this DLT. Furthermore, the antitumor activity of XR5000 correlates with the total dose given,6 and at high concentrations, XR5000 inhibits its own cytotoxicity, whereas lower doses given for prolonged periods are more cytotoxic.16,17 Other factors warranted a trial of prolonged infusion for this drug. Expression of topoisomerase II Radiotracer studies with positron emission tomography (PET) can provide direct information on tumor and normal tissue pharmacokinetics.21,22 The information provided by such studies may be useful in predicting drug activity and toxicity. This novel process of integrating tissue pharmacokinetic assessment into early development of an anticancer agent was applied in the development of the 3-hour infusion regimen of XR5000.12,23 That study demonstrated [11C]XR5000 uptake in a variety of tumors, including brain tumors. A PET pharmacokinetics study was incorporated into the present study with the aim of evaluating tumor and normal tissue pharmacokinetics of [11C]XR5000. In this study, XR5000 was given as a 120-hour continuous infusion, via a central venous catheter, in repeated cycles of once every 3 weeks. The aims were to determine the MTD and the plasma and tumor pharmacokinetics and toxicities of XR5000. This would determine the optimal dose for phase II studies and provide insights into the pharmacokinetic merits of the continuous infusion approach.
Eligibility Criteria Inclusion criteria included the following: histologically confirmed metastatic solid tumor refractory to conventional therapy, or for which there was no standard therapy; age more than 18 years; World Health Organization (WHO) performance status 0, 1, or 2 and life expectancy of at least 3 months; adequate hemopoietic reserve, defined as a granulocyte count of more than 2 x 109/L and platelet count more than 100 x 109/L; adequate renal function, defined as serum creatinine less than 0.14 mmol; and adequate hepatic function, defined as serum bilirubin less than 1.5 times the upper limit of normal, with transaminases and alkaline phosphatase less than two times the upper limit of normal and normal prothrombin time. Major exclusion criteria were as follows: pregnant, lactating, or not taking adequate contraceptive precautions; chemotherapy or radiotherapy within the previous 4 weeks (at least 6 weeks since treatment with nitrosoureas or mitomycin C); major surgery within the previous 14 days, and/or intercurrent or serious infection within the previous 28 days; life-threatening illness unrelated to cancer; and a history of ischemic heart disease or abnormal electrocardiogram (ECG).
Study Design The MTD was defined as the dose at which DLTs occurred in one third or more of the patients. DLTs were defined as white blood count nadir less than 0.5 x 109/L or a platelet nadir less than 50 x 109/L; failure to recover by day 35 after the previous treatment to a granulocyte count of 1.5 x 109/L or a platelet count of 100 x 109/L; or other National Cancer Institute Common Toxicity Criteria (CTC; version 1) grade 3 or grade 4 nonhematological toxicity (except for alopecia or nausea and vomiting), unless considered unrelated to XR5000.
Trial Medication and Administration XR5000 was administered as a 120-hour continuous intravenous (IV) infusion using an ambulatory infusion pump (either the WalkMed 350 pump in Oxford or the WalkMed 410 pump in Glasgow) and a previously inserted Gish Hickman line. The drug was given undiluted in the pump. The infusion is stable for at least 7 days in a Medex IPR infusion set (BARD, Inc., Summit, NJ), Lectro Spiral Vygon extension tube (BARD, Inc.), and a Gish Hickman catheter (BARD, Inc.). The bag and connecting tubing were protected from light. All patients were hospitalized during the infusion.
Treatment
Toxicity and Response Evaluation
Pharmacokinetics XR5000 concentrations were determined by high-performance liquid chromatography (HPLC). In brief, 200 µL of plasma was added to 0.9 mL of acetonitrile and 50 µL of internal standard, mixed, and centrifuged at 10,000 rpm for 10 minutes at 4°C. The supernatant was dried, and the residue suspended in 200 µL of mobile phase and centrifuged for 3 minutes at 10,000 rpm, and then the supernatant was injected onto the HPLC column. The system used a Brownlee RP18 precolumn (Perkin-Elmer, Shelton, CT) and Phenomenex Primasphere 5 µm C18, 250-mm analytic column (Perkin-Elmer). The mobile phase was 28% acetonitrile and 10 mmol/L TEAP (aqueous triethylamine solution adjusted to pH 2 with orthophosphoric acid; 1 M stock diluted 1:100). The flow rate was 1 mL/min, and fluorescence detection was used (excitation 360 nm, emission > 450 nm). The assay was linear between 0.01 and 10 µmol/L, and the coefficient of variation was less than 10% for all quality control samples. All pharmacokinetic data are expressed in terms of the dihydrochloride salt.
Pharmacokinetic Analyses
PET Pharmacokinetic Studies
PET Scanning
Analysis of PET Data
Statistics
Ethical Considerations
Twenty-four patients were entered onto the study, and a total of 67 cycles were administered. Patient demographics are listed in Table 1  . Three patients were treated at each dose cohort up to 2,240 mg/m2/120 hours XR5000. Three patients entered the 2,240 mg/m2/120 hours cohort, and a fourth, who initially received 3,010 mg/m2/120 hours, was dose reduced because of DLT to 2,240 mg/m2/120 hours. Initially, three patients were treated at the 3,010 mg/m2/120 hours XR5000 level. Because none of these developed a DLT, the next patient received 4,060 mg/m2/120 hours. This patient was withdrawn from the study after 48 hours treatment because of grade 4 toxicity (chest and abdominal pain). Because this toxicity was so severe, no further patients were treated at this dose level, and the preceding 3,010 mg/m2/120 hours dose cohort was expanded to include a total of eight patients. The number of cycles and patients treated were as follows: one cycle, five patients; two cycles, seven patients; three cycles, four patients; four cycles, four patients; five cycles, one patient; and six cycles, two patients.
Hematological Toxicity Hematological toxicities are shown in Table 2 . Clinically significant hematological toxicity was uncommon. One patient receiving 3,010 mg/m2/120 hours developed grade 4 neutropenia and grade 3 thrombocytopenia during the first treatment cycle. Despite dose reduction to 2,240 mg/m2/120 hours, this recurred in the second cycle, and the patient was withdrawn from the study.
Nonhematological Toxicity The major event and DLT in this study was grade 4 chest and abdominal pain, affecting the single patient treated with XR5000 at 4,060 mg/m2. This pain developed 48 hours after commencing therapy and was of rapid onset. The pain started in the shoulders and radiated to the chest, abdomen, and scrotum. There was attendant marked pallor and sweating, but the vital signs were unchanged and normal. The infusion was stopped and the symptoms resolved within 1 hour. There were no attendant ECG or cardiac enzyme changes. The plasma XR5000 level, 2,040 ng/mL, checked 25 minutes after the infusion was stopped, was well in excess of that predicted by linear pharmacokinetics. No other patient developed chest pain of this nature during the study.
Five patients had venous thrombosis affecting either the brachiocephalic or jugular veins or superior vena cava (Table 3
Significant ECG changes were observed in three patients. One (3,010 mg/m2/120 hours) had transient T-wave inversion in the V2 lead, and although this patient had transient mild chest pain, this inversion was the result of the underlying tumor and was not ischemic in nature. None of the ECGs of the other seven patients who received XR5000 3,010 mg/m2/120 hours showed evidence of myocardial ischemia. One patient (3,010 mg/m2/120 hours) had ECG changes suggestive of pericarditis, attributed to mediastinal tumor invasion, rather than the drug. A third patient (2,240 mg/m2/120 hours) developed T-wave inversion and biphasic T-waves suggestive of myocardial ischemia/subendocardial infarction. At autopsy, however, there was no macroscopic or microscopic evidence of myocardial infarction or ischemia. Minor and transient prolongation of the QTc interval, just reaching abnormality (0.44 seconds), was observed in nine patients.
Responses
XR5000 Plasma Pharmacokinetics After the start of treatment, plasma concentrations of XR5000 increased rapidly, and Cmax was observed between 8.6 and 121.8 hours (Tmax). Steady-state levels were attained within the first 24 hours. XR5000 exhibited a terminal elimination phase half-life of 1.64 to 2.72 hours (mean, 2.08 ± 0.44 hours) and volume of distribution at steady-state range of 84 to 207 L/m2 (mean, 138.1 ± 49.9 L/m2). Mean Cmax and AUC at the MTD were 3.3 ± 1.5 µM/h and 319 ± 161 µM/h, respectively. Mean plasma clearance was 68.5 ± 30.3 L/h, representing interpatient variability of 44%.
Systemic exposure (Cmax and AUC) increased with increasing dose (Fig 1A and B
There was no evidence of changes in XR5000 pharmacokinetics with repeated dosing in the seven patients who received a second treatment cycle. Overall, the estimated pharmacokinetic parameters revealed moderate intersubject variability (up to fourfold differences in the AUC0–t (where t is the time to last sample) within the same dose group), but intrasubject variability was low.
PET Tumor and Normal Tissue Pharmacokinetics
Inspection of cumulative PET images, derived from the summing of all dynamic images (0 to 90 minutes), showed that [11C]XR5000 distributed to all tumor types studied (eg, Fig 2
Comparison of tissue parameters between tracer alone ([11C]XR5000-PET between courses) and combination studies ([11C]XR5000-PET during steady-state of 120 hours infusion) was performed for vertebral body (representing bone marrow) and tumors only, as fewer than three samples were available for the other tissues. No differences in tumor blood flow (mean ± SD milliliter blood/milliliter tissue/min) were observed between tracer-alone (0.144 ± 0.07) and combination (0.157 ± 0.06) studies (P = .15). In general, higher Cmax, AUC, and SUV were seen in both vertebral body and tumors in the combination studies compared with tracer alone studies (Table 4 ). Of these studies, the Cmax (mean ± SD; tracer alone v combination studies) for vertebral body (0.635 ± 0.21 v 0.806 ± 0.19 x 10-4 m2/mL) was significantly higher in combination studies (P < .05). The radiotracer AUC (mean ± SD; tracer alone v combination studies) in tumors (0.209 ± 0.04 v 0.242 ± 0.04 m2/mL/sec) was also significantly higher in combination studies (P < .05).
This study shows that XR5000 administered by 120-hour infusion produces potentially effective plasma drug concentrations with acceptable toxicity. PET pharmacokinetic studies with 11C-labeled drug were feasible and confirmed distribution and quantitation of XR5000 into tumors. Saturation of tumor exposure was not, however, reached at the MTD. This study was designed to test the hypothesis that a plasma tumoricidal dose of XR5000 could be achieved with acceptable toxicity by prolonging the length of drug administration. The toxicity profile was improved compared with the previous 3-hour infusion. A higher XR5000 dose intensity at the MTD, 3,010 mg/m2/120 hours every 21 days, was achieved with considerably less toxicity as compared with 2,400 mg/m2 every 21 days in the three-times-daily infusion study and 750 mg/m2 every 21 days in the one-time-daily infusion study. One patient developed grade 4 chest and abdominal pain at the 4,060 mg/m2/120 hours dose level. Because of this episode, the preceding 3,010 mg/m2/120 hours dose cohort was expanded to eight patients, none of whom developed this problem. The etiology and nature of the pain is unclear. The characteristics were not cardiac, there were no ECG or cardiac enzyme changes of myocardial damage, and the patient made a full recovery within 1 hour of stopping the drug. Apart from the patient who developed chest and abdominal pain, XR5000 was generally well tolerated. The 120-hour infusional schedule has significant plasma pharmacokinetic advantages over shorter administration schedules. The mean AUC achieved at the MTD (3,010 mg/m2) was about seven times that achieved at the MTD in the 1-day, 3-hour infusion study.14 Cmax at the MTD in the current study, 3.3 ± 1.5 µM, was approximately 25% of that of the 3-hour infusion studies.12,14 This compares with the mean IC50 of XR5000—2.1 µM (range 0.42 to 5.4 µM)—against the NCI 60 tumor cell line panel.4 Although the Cmax in this study did not greatly exceed the mean IC50, prolonged exposure (72 hours) to XR5000 produced cell kill rates exceeding 99.9% at submicromolar concentrations.17 In addition, XR5000 induced maximal DNA-protein cross-links at concentrations between 1 and 5 µM.28 Furthermore, in vitro, the optimal cytotoxicity concentration, at least for LLTC cells (lung carcinoma) is 3 µM. As concentrations rise above this, XR5000 inhibits its own cytotoxicity.16 These preclinical studies indicate that the Cmax concentrations in this study could optimize tumor cell kill. An important limitation of conventional pharmacokinetics analyses is that they reflect drug levels in the plasma rather than normal tissues or tumor. In this study, we attempted to overcome this problem by evaluating the normal tissue and tumor pharmacokinetics at the MTD by designing a novel PET pharmacokinetic approach. Anticancer drugs can be labeled with positron emission isotopes such as carbon-11. After injection, detection and quantitation of the minute amounts of emitted radiation can be used to derive tumor and normal tissue pharmacokinetics. Paradigms designed to perturb the kinetics can then be used to investigate factors affecting drug kinetics. In this study, our priority PET pharmacokinetic questions were: Was there tumor uptake above plasma levels; was tumor and normal tissue exposure to drug a nonsaturated process at MTD, indicating that further exposure was possible if a delivery schedule to overcome toxicity could be developed; and was tumor blood flow an important determinant of drug delivery and, hence, pharmacokinetic variability in tumors? The PET pharmacokinetic data showed that [11C]XR5000 and its metabolites distributed well into all the tumor types studied. One limitation of PET is its inability to distinguish the radiolabeled parent from its metabolites because the tissue signal in PET studies comprises the total radiotracer (consisting of [11C]XR5000 and [11C]metabolites). Together with complementary rodent data indicating that [11C]XR5000 is the major contributor of tumor radioactivity at 5 minutes, the data infer that [11C]XR5000 is taken up by tumors. Despite similar Tmax values between tumors and surrounding normal tissues, the magnitude of radiotracer uptake (Cmax, AUC) was lower for tumors. This could be caused by low blood flow (< 0.25 mL/mL tissue/min) and, hence, tumor drug delivery. Lower tracer uptake was also observed in studies with 5[18F] fluorouracil.22 The decrease in drug delivery seen in large, solid tumors may contribute to lower tumor exposure, even for lipophilic drugs such as XR5000. There was an increase in tumor radiotracer exposure (AUC) in the combination studies. In our previous [11C]XR5000 PET pharmacokinetic study,23 where more patients were evaluated (n = 29), normal tissue and tumor [11C]XR5000 pharmacokinetics were compared in different groups of patients at tracer doses ([11C]XR5000 given alone; n = 24) and at three escalating phase I doses (36 to 165 mg/m2; MTD 800 mg/m2) using the 3-hour infusion regimen ([11C]XR5000 given midway during the infusion; n = 5). In that study, we observed an increase in tumor pharmacokinetic parameters, contrasting with a decrease in normal tissue parameters when [11C]XR5000 was administered during the infusion of XR5000.23 This finding was attributed to saturable processes in drug uptake, tissue binding, or metabolism in normal tissues and an absence of such processes in tumors. Although the number of normal tissue samples in the present study was limited, the increase in tumor exposure could be attributed to a similar differential in saturable processes in tumors and normal tissues at the doses of XR5000 studied. These findings would indicate that maximal tumor drug levels were not attained at the MTD and that if less-toxic delivery schedules could be found, a further therapeutic advantage and increased tumor drug level may be achievable. Uptake of [11C]XR5000 and its metabolites was seen in normal tissues, including kidney, liver, spleen, and vertebral body. Of importance to normal tissue toxicity are vertebral body tracer kinetics, which may correlate with myelosuppression. As observed in our previous study,23 the TAC profile, Cmax, and AUC for vertebral body was in the lower range, compared with other normal tissues. These findings would predict a low incidence of myelotoxicity with the 120-hours infusion regimen of XR5000, which was confirmed by the hematological data. Because of the limited number of patients recruited to the PET study, resulting in fewer than three samples for other normal tissues, we were unable to compare other normal tissues such as the myocardium. In conclusion, this study demonstrates the value of plasma and PET tumor and normal tissue pharmacokinetic information in developing rational dose schedules aimed at increasing tumor exposure to an anticancer drug while reducing normal tissue exposure and clinical toxicity. For XR5000, by extending the infusion time, clinical toxicity was reduced and the plasma AUC was increased. On the basis of plasma pharmacokinetics, the recommended dose for phase II studies of XR5000 is 3,010 mg/m2/120 hours once every three weeks, at which potentially therapeutic plasma levels were attained. However, tumor exposure was still limited by poor tumor blood flow, and saturation of tumor exposure was not reached at the MTD. PET pharmacokinetic studies should be considered in addressing specific kinetic questions in drug development studies.
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23. Saleem A, Harte RJ, Matthews JC, et al: Pharmacokinetic evaluation of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in patients by positron emission tomography. J Clin Oncol 19:1421–1429, 2001 24. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207–214, 1981[CrossRef][Medline] 25. Brady F, Luthra SK, Brown G, et al: Carbon-11 labelling of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and determination of plasma metabolites in man. Appl Radiat Isot 48:487–492, 1997[CrossRef][Medline] 26. Brooks RA, Di Chiro G: Theory of image reconstruction in computed tomography. Radiology 117:561–572, 1975[Abstract] 27. Robb RA, Hanson DP: A software system for interactive and quantitative visualization of multidimensional biomedical images. Australas Phys Eng Sci Med 14:9–30, 1991[Medline] 28. Schneider E, Darkin SJ, Lawson PA, et al: Cell line selectivity and DNA breakage properties of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide: Role of DNA topoisomerase II. Eur J Cancer Clin Oncol 24:1783–1790, 1988[CrossRef][Medline] Submitted January 31, 2001; accepted September 23, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, which is sensitive to XR5000,
), spleen (
), kidney (—), lung (x), vertebral body (
), and tumor (•)
