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© 1999 American Society for Clinical Oncology Phase I Trial of Intravenous Thymidine and Carboplatin in Patients With Advanced CancerFrom the University of Wisconsin Comprehensive Cancer Center, Madison, WI; Medical University of Lübeck, Lübeck, Germany; University of Kentucky, Lexinton, KY; and University of Colorado Cancer Center, Denver, CO. Address reprint requests to H. Ian Robins, MD, PhD, Department of Medicine, University of Wisconsin Comprehensive Cancer Center, K4/666, 600 Highland Ave, Madison, WI 53792; emailhirobins{at}facstaff.wisc.edu
PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m2 in a phase I trial. PATIENTS AND METHODS: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m2 (n = 3); 300 mg/m2 (n = 7); 350 mg/m2 (n = 4); 400 mg/m2 (n = 3); 480 mg/m2 (n = 10); and 576 mg/m2 (n = 5). At the maximum-tolerated dose (480 mg/m2), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy. RESULTS: Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m2-dose level, and disease stabilization (7 months) at the 400-mg/m2-dose level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m2-dose level. CONCLUSION: The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.
THYMIDINE, A NATURALLY occurring nucleoside, is metabolized intracellularly to thymidine triphosphate. Thymidine triphosphate allosterically modulates ribonucleotide reductase, resulting in deoxycytidine starvation with cessation of DNA synthesis and repair and eventually cell death, and increased levels of deoxyguanosine triphosphate, an inhibitor of DNA polymerase.1-4 Thymidine also potently inhibits poly(ADP-ribose) polymerase (PARP), a key enzyme involved in DNA repair,1,3,5-7 which consumes nicotinamide adenine dinucleotide (NAD+) as its primary rate-limiting substrate. Thymidine preferentially kills neoplastic cells in vitro and induces complete and partial regression of a wide variety of human tumor xenografts in nude mice.1,2,5 In clinical studies, prolonged thymidine infusions produced brief responses in heavily pretreated patients with acute T-cell leukemia, mycosis fungoides, and acute myelogenous leukemia.2,8-10 These prolonged, high-dose infusions (5 to 29 days at 60 to 240 g/m2/d) were also myelosuppressive,2,8,10 and clinical investigation of thymidine was abandoned. Interestingly, however, thymidine myelosuppression at high doses is primarily a function of the duration of administration.1,2,8-12 Accordingly, myelosuppression is minimal or even zero when high thymidine doses are given for only 1 to 2 days in murine models and in humans.1,2,11,12 More recently, it has been shown that 24-hour thymidine exposures retain substantial antineoplastic efficacy in vitro.1,3,5 Significantly, thymidine exposures of just 4 to 24 hours potently enhance carboplatin cytotoxicity in vitro for a variety of cell types, including human T-cell acute leukemia, human Burkitt's lymphoma, and rat glioblastoma, as well as for cisplatin in human T-cell acute leukemia and the LoVo human colon adenocarcinoma.1,5,13 Dose-modifying factors range from approximately 2 to 3.5.1,5 The thymidine-carboplatin interaction increases steadily with longer thymidine exposures up to 16 hours and then remains constant.1 The sensitization effect is the same for thymidine concentrations between 100 and 1,000µg/mL,1,5 equal to the range of human serum thymidine levels at doses of 60 to 240 g/m2/d.1,2 In vivo studies that used normal B6D2 F1 mice showed that 24-hour thymidine infusions (280µg/mL in murine serum) are not myelosuppressive and also do not enhance hematologic or other normal tissue toxicities of carboplatin.13 This was at a dose corresponding to 75 g/m2/d in humans,12 the thymidine dose used as 5-day infusions in phase II clinical studies.2,8,9 This observation suggests that 24-hour thymidine infusions could enhance the antineoplastic effects of carboplatin without comparable increases in normal tissue toxicity. Based on the aforementioned studies and considerations, a phase I study was initiated after full institutional review board approval was obtained. The primary goal was to evaluate the clinical toxicity of a 24-hour thymidine infusion (75 g/m2) by itself and in combination with escalating carboplatin doses (200, 300, 350, 400, 480, and 560 mg/m2 administered intravenously over 20 minutes 20 ± 0.5 hours into the thymidine infusion) compared with carboplatin alone in patients with advanced malignancies. This time point for carboplatin administration was selected to maximize PARP inhibition. The first seven patients received thymidine alone followed 3 weeks later by thymidine and carboplatin and then 4 weeks later by carboplatin alone. Subsequent patients proceeded directly to combined thymidine/carboplatin therapy followed 4 weeks later by carboplatin alone. After the initial evaluation period, patients who continued therapy (without evidence of progressive disease) received combined-modality treatment only. When the maximum-tolerated dose (MTD) was identified, patients were randomized between the sequencing of carboplatin alone versus carboplatin/thymidine during the first two cycles. In the context of the study, independent variables evaluated included toxicity, tumor responses, plasma levels of thymidine and its chief metabolite thymine, and the pharmacokinetics of carboplatin. Additionally, to gain mechanistic insights into thymidine inhibition of DNA-repair (via PARP), sequential determinations of peripheral lymphocyte NAD levels were obtained. The present report summarizes the results of this investigation.
Patient Selection Patients were  18 years of age and were required to have a histologically confirmed advanced or metastatic malignancy with no probability of cure and not amenable to conventional treatment. Patients also needed an Eastern Cooperative Oncology Group performance status14 of 2 or better, either measurable or assessable disease, and a life expectancy of at least 12 weeks. Written informed consent was obtained from all patients. Also required were an adequate bone marrow function (WBC count 3.4 x l03/µL and platelet count > 100 x l03/µL), adequate hepatic function (total bilirubin level  1.5 mg/100 mL) and liver function tests (< three times normal; normal alkaline phosphatase laboratory range, 35 to 130 U/L; normal lactate dehydrogenase laboratory range, 90 to 200 U/L; normal serum glutamate transferase range, 0 to 50 U/L), and adequate renal function (creatinine level < 1.5 mg/dL or creatinine clearance 60 mL/min; blood urea nitrogen 30 mg/dL), with calcium and electrolytes within normal limits. For patients in whom carboplatin pharmacokinetics was measured, 12- or 24-hour creatinine clearance collections were performed before each of the first two carboplatin doses (thymidine plus carboplatin and then carboplatin alone).
Patients with a history of congestive heart failure (or physical signs of the same), cardiac dysrhythmia that required ongoing medical intervention, myocardial infarction within the past 6 months, or uncontrolled hypertension were ineligible. Patients with valvular heart disease or with a history or electrocardiographic evidence of myocardial infarction were eligible if the radionuclide ejection fraction was Because of the documented toxicity of thymidine for human T cells, patients with AIDS or known prodrome of AIDS were ineligible. Patients with more than 25% of their marrow irradiated were not eligible for the study. Patients were enrolled onto the study between 1993 and 1997. A demographic profile of the treated patient population is listed in Table 1.
Treatment Plan
Thymidine was prepared at a concentration of 30 mg/mL in a solution of 0.6% NaCl solution so as to provide 75 g/m2 over 24 hours (4.25 L over 24 hours, or 177 mL/h in a 1.7-m2 person). Serum electrolytes, including Mg++, were checked within 1 week before initiating the thymidine infusion and at the end of the infusion. Carboplatin was dissolved in 100 mL of 5% dextrose water and administered as a 20-minute intravenous infusion without interrupting the thymidine infusion. Carboplatin and thymidine were administered at separate venous access sites. The carboplatin injection was begun after 20 ± 0.5 hours of thymidine infusion. The carboplatin dose was escalated with six dose levels (Fig 1). Patients received antiemetic medications and other symptomatic therapies according to standard guidelines. The initial carboplatin dose level of 200 mg/m2 was chosen because of (1) the potential carboplatin dose-modifying effect of thymidine and (2) the potential for some degree of thymidine myelosuppression in addition to the toxicity of carboplatin. Patients were monitored for hematologic or serologic evidence of myelosuppression, hepatic injury, renal injury, and electrolyte disturbances, as well as for clinical evidence of any other toxicity using the Division of Cancer Treatment, National Cancer Institute Common Toxicity Criteria. Complete and partial responses were evaluated using standard Eastern Cooperative Oncology Group criteria.14
Pharmacologic Studies Platinum assay. The platinum was assayed using a well-validated procedure that has been used previously for platinum-containing pharmacokinetic samples.15 Platinum in plasma and ultrafiltered plasma was assayed by furnace atomic absorption spectrophotometry using a Varian SpectrAA-20 with GTA-96 furnace and D2 background correction (Varian Associates, Sunnyvale, CA). The analysis program used was as follows: dry 85 to 120°C, ramp for 70 seconds, pyrolize 750 to 1,100°C for 45 seconds, and atomize at 2,700°C for 5 seconds. Samples were diluted as necessary with a matrix of 0.1% nitric acid/0.2% Triton X-100 (vol/vol), and 15-µL aliquots were assayed. All samples were assayed in duplicate. A platinum standard curve was constructed from diluted American Chemical Society standard platinum over the concentration range 50 to 200 ng/mL. The limit of detection is 4 ng/mL platinum in the sample, and the sample limit of quantitation is 10 ng/mL. The coefficient of variation in duplicate samples averaged 1.5%. The coefficient of variation in replicate assays of platinum-containing plasma or ultrafiltrate was 3.2% for a 200-ng/mL standard and 9.0% for a 20-ng/mL standard (n = 8 over 8 months). Thymidine/thymine assay. Thymidine and thymine were assayed by reverse-phase high-performance liquid chromatography using an isocratic mobile phase of 15% methanol/85% water pumped at a flow rate of 1.2 mL/min through a Waters Nova-Pak RCM 8 x 10 column (Waters Corporation, Milford, MA), with ultraviolet detection at 266 nm. Plasma samples (100 µL) were prepared by deproteinization with 4 vol methanol after addition of the internal standard 5-bromouracil. The supernatant was diluted with 4 vol mobile phase before chromatographic separation. The plasma standard curve was linear from 0.1 to 5 mmol/L. Extraction efficiency was close to 100%. The intraday variability in the assay was less than 5% over the concentration range, and the interday variability was less than 10%. Pharmacokinetic methods. For carboplatin, each set of concentration-time data for ultrafiltrable platinum (UF-Pt) was fit to a biexponential model using PKAnalyst (MicroMath, Inc, Salt Lake City, UT). Zero time intercepts were corrected for infusion time, and the pharmacokinetic parameters were calculated using standard relationships.16 For thymidine, the steady-state concentration of thymidine and thymine were calculated as the mean of the 20- and 22-hour values. Clearance of thymidine was calculated as (infusion rate)/(steady-state concentration).
NAD Determinations
Nucleotides were extracted as described previously.18 The NAD+ was extracted from lymphocytes immediately after blood sample collection using 0.5 mol/L ice-cold HCIO4; the sample was neutralized with 1 mol/L KOH and 0.33 mol/L K2HPO4. The samples were stored at –70°C until NAD could be determined. The NAD pools were measured by an enzymatic cycling assay.19 NAD values are presented as picomoles per 107 cells.
Carboplatin Pharmacokinetics The first patients entered onto the study received thymidine alone as their first treatment. Subsequent patients received the combination cycle of carboplatin plus thymidine first, followed 4 weeks later by a cycle of carboplatin alone (Fig 1). At the end of the study, additional patients at the 480-mg/m2 dose level received carboplatin alone first, followed by the combination cycle. Overall, 19 paired sets of carboplatin pharmacokinetic samples from patients who received both the combination cycle and carboplatin alone were available for analysis over the dose range 200 to 480 mg/m2. There was a total of seven paired courses at the 480-mg/m2 dose level: four in which the patients received the combination first and carboplatin alone second, and three in which the patient received the courses in reverse order. For these courses, there was no statistical difference in any pharmacokinetic parameter, whether the carboplatin alone was administered first or second. Over the course of the trial, pharmacokinetic parameters were determined for an additional six unpaired cycles (four combination and two carboplatin alone). Taken together, the area under the curve (AUC) of UF-Pt increased linearly with dose, and the relationship between dose and AUC was identical for both cycles (Fig 3). In addition, the observed AUC of UF-Pt correlated well with the AUC predicted using the Calvert relationship,20 as shown in Fig 4. All pharmacokinetic parameters are listed in Table 2. No parameter other than AUC was dose dependent, and thymidine did not seem to significantly affect the pharmacokinetics of carboplatin-derived UF-Pt or the plasma protein binding. These pharmacokinetic parameters are very similar to those previously reported for carboplatin.15 It is noteworthy that the pharmacokinetics of patients with brain tumors who received dexamethasone and/or antiseizure medications was not different from that of the study population as a whole.
Thymidine/Thymine Pharmacokinetics
Pharmacodynamics and Hematologic Toxicity
We also applied the Egorin equation for predicting platelet decrease22 to the platelet data for all cycles (Fig 6). Although the correlation between predicted and observed decrease in platelet count was significant (P < .001) for both the combination cycles and the carboplatin-alone cycles, the correlation coefficient was much smaller for the combination cycles (r = .634 v .832), indicating a smaller-than-expected decrease in platelet counts. When we compared the slopes for combination therapy line versus the carboplatin (F test; parallel regression analysis), the difference was not statistically significant (P = .084) but was suggestive of less thrombocytopenia with combination therapy.
In summary, thrombocytopenia was dose-limiting for carboplatin. There were no incidences of bleeding or febrile neutropenia in the course of the study. Neutropenia was not dose-limiting (Fig 5), and thymidine had no effect on WBC counts (data not shown).
Nonhematologic Toxicity With carboplatin alone, mild headache or neuromotor toxicity was associated with approximately 12% of treatments. Carboplatin-related nausea and vomiting was dose-related. There was no suggestion that it was enhanced by thymidine. The incidence of grade 1 or 2 nausea and vomiting was 0% at levels I and II, 75% at level III, and 100% at levels IV and V. At level VI, 80% of patients experienced grade 1 or 2 nausea and vomiting, and 20% experienced grade 3. Disease-related toxicity included three patients with advanced hepatic disease who experienced hyperbilirubinemia at a time of disease progression.
NAD+ Studies
Disease Response to Therapy Based on preclinical modeling described, in part, in the Introduction,5,23 patients with high-grade gliomas (n = 6) were a target population of this phase I study. In this regard, we observed a complete response in a 42-year-old man with an anaplastic astrocytoma (21 months) who received eight cycles of therapy; a partial remission (14 months) was observed in a 56-year-old patient with a glioblastoma multiforme who received four cycles of therapy. Both of these remissions were observed at the 480-mg/m2 dose level. Stable disease (7 months) was observed in a 56-year-old man with glioblastoma multiforme who received three cycles of therapy (400 mg/m2). Three patients with glioblastoma multiforme were treated at dose level II (300 mg/m2): one patient (47-year-old man) was not assessable because he was lost to follow-up after showing dramatic clinical improvement after the first cycle of therapy. The other two patients (44-year-old man and 33-year-old woman) were observed to have progressive disease after two and three cycles of therapy, respectively.
A major objective of this study was evaluation of potential interactions between thymidine and carboplatin. The results demonstrated the level of thymidine and thymine measured at the conclusion of a 24-hour infusion was consistent with the literature21 and not affected by carboplatin administration (Table 3). Similarly, a careful analysis of carboplatin pharmacokinetics demonstrated that the parameters studied were consistent with previous studies15,20 and not affected by thymidine infusion. A corollary finding of this phase I study is that thymidine had an apparent effect in protecting against carboplatin-induced myelosuppression, ie, thrombocytopenia (Table 4; Figs 5 and 6). Several possible mechanisms could explain this observation. Thymidine is widely used to synchronize cells in S phase with little cell death; such synchronization also occurs in vivo for human hematopoietic progenitor cells.10,24 Because carboplatin has little cell-cycle specificity, such synchronization would not be expected to affect myelotoxicity. However, the cessation of replication of progenitor hematopoietic cells resulting from such synchronization might allow additional time for repair of carboplatin-DNA adducts, resulting in relative myeloprotection. Alternatively, sparing the NAD pool by inhibiting PARP may have protected progenitor hematopoietic cells from energy losses and/or apoptosis. In this regard, an earlier phase I study by Schultz et al25 in 1996 investigated carmustine in combination with a 48-hour infusion of thymidine. The rationale for this study was also based on inhibition of PARP by thymidine. Both the carmustine dose (given as a 1-hour infusion) and the thymidine dose were varied. The time of carmustine administration was not specified. Thymidine did not affect myelosuppression (the study design did not allow for the observation of a myeloprotective effect). Neurologic side effects of thymidine, which were mild and reversible, were similar to those observed in our trial. Schultz et al25 predicted that thymidine might enhance carmustine myelosuppression. Our preclinical murine modeling of peripheral blood counts12 suggested that this should not be the case; thus, the results obtained here were expected. To study the mechanisms of action for thymidine and/or carboplatin, we examined peripheral lymphocytes from treated subjects (Fig 2). We tested the hypothesis that thymidine interferes with cell survival after carboplatin treatment via inhibition of PARP by assessing NAD+ levels as an indirect measure of PARP activity. The pharmacokinetic data showed that circulating thymidine levels achieved were nearly 50 times the Ki for PARP. Thus, the observed increases in lymphocyte NAD during the 24-hour thymidine infusion and after carboplatin treatment (Fig 2A) are consistent with inhibition of NAD hydrolysis by thymidine, because carboplatin treatment alone (Fig 2B) resulted in a severe loss of NAD 2 hours after treatment. By 24 hours after treatment, NAD decreased to approximately 10% of its initial value. This loss was limited to approximately 25% of initial values in thymidine-treated subjects despite the fact that the samples were taken at approximately 11 half-lives of thymidine clearance. Because the maximum concentration of thymidine reached was 1.8 to 1.9 mmol/L and the half-life was 120 minutes, a thymidine concentration exceeding the Ki (approximately 40 µmol/L) for PARP6 should have been maintained for approximately 10 hours. Thus, the observed changes in NAD levels are highly consistent with inhibition of PARP by thymidine.
There is a large body of literature demonstrating that inhibition of PARP by inhibitors or genetic approaches enhances the cytoxic effects of alkylating agents and/or radiation. The data obtained in this study that correlate biochemical events in lymphocytes of treated patients to clinical outcome are particularly encouraging with reference to our patients with high-grade gliomas. Preclinical investigations5,23 of this histologic diagnosis suggested a therapeutic application for this multimodality therapy: in vitro studies demonstrated that 24-hour exposure to thymidine was cytotoxic to C6 glioma cells at concentrations clinically achieved in this study. In addition, thymidine synergistically enhanced carboplatin cell kill. In this clinical trial, we observed two responses and one disease stabilization in three of three patients with glioma who were treated in the presumed therapeutic dose range of the study (ie, carboplatin In conclusion, the data presented here suggest that limiting poly(ADP-ribose) metabolism during carboplatin therapy may be a clinically effective approach for certain malignancies, eg, glioma. Further studies to characterize ADP-ribose polymer metabolism and drugs that are effective for this target seem warranted.
Supported in part by the Cancer Research Institute, New York, NY; Northwestern Mutual Life Foundation, Milwaukee, WI; The Kathleen Reader Neuro-Oncology Fund; and grants no. MOI RR03186, UOI CA 70094, UOI CA62491, CA 65579, and P30CA14520-26 from the National Institutes of Health, Bethesda, MD. We greatly appreciate the statistical support of Dr Jeffrey Douglas (University of Wisconsin Comprehensive Cancer Center, Madison, WI) and the technical support of Marcia Pomplun and Amy Wahamaki.
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Robins HI, Cohen JD, Schmitt CL, et al: Phase I clinical trial of carboplatin and 41.8°C whole body hyperthermia in cancer patients. J Clin Oncol 11:1787-1794, 1993 16. Gibaldi M, Perrier D: Multicompartment models, in Pharmacokinetics (ed 2). New York, NY, Dekker, 1982, pp 45-111 17. Berger NA, Berger SJ, Sitorski GW, et al: Amplification of pyridine nucleotide pools in nitrogen-stimulated human lymphocytes. Exp Cell Res 137:79-88, 1982[Medline] 18. Jacobson EL, Jacobson MK: Pyridine nucleotide levels as a function of growth in normal and transformed 3T3 cells. Arch Biochem Biophys 175:627-634, 1976[Medline] 19. Jacobson EL, Lange RA, Jacobson MK: Pyridine nucleotide synthesis in 3T3 cells. J Cell Physiol 99:417-426, 1977 20. Clvert AH, Newell DR, Gumbrell LA: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989[Abstract] 21. Zaharko DS, Bolten BJ, Kobayashi T, et al: Thymidine and thymine in biologic fluids during high-dose infusions of thymidine in mice, monkeys, and man. Cancer Treat Rep 63:945-949, 1979[Medline]
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Egorin MJ, Van Echo DA, Tipping SJ, et al: Pharmacokinetics and dosage reduction of cis-diammine (1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function. Cancer Res 44:5432-5436, 1984 23. Cohen JD, Robins HI, Javid MJ: Radiosensitization of C6 glioma by thymidine and 41.8°C hyperthermia. J Neurosurg 72:782-785, 1990[Medline] 24. Fox RM: Changes in deoxynucleoside triphosphate pools induced by inhibitors and modulators of ribonucleoside diphosphatereductase activity, in Cory JG, Cory AH (eds): Inhibitors of Ribonucleoside Diphosphate Reductase Activity. New York, NY, Pergamon Press, 1989, pp 113-126 25. Schultz MZ, Sandler AB, Durivage HJ, et al: A phase I pilot study of BCNU plus thymidine in patients with refractory cancer. Cancer Invest 14:218-224, 1996[Medline] Submitted October 26, 1998; accepted May 14, 1999. This article has been cited by other articles:
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
At the determined MTD (ie, 480 mg/m2 carboplatin), five patients received carboplatin plus thymidine first (followed by carboplatin) and five patients received carboplatin first (followed by carboplatin plus thymidine).
) or in combination with thymidine (
) is shown. P < .001, r = .812, n = 23 for carboplatin alone; P < .001, r = .826, n = 21 for carboplatin plus thymidine.
