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© 1999 American Society for Clinical Oncology Phase I and Pharmacologic Study of the Tyrosine Kinase Inhibitor SU101 in Patients With Advanced Solid Tumors From the Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX; South Texas Oncology and Hematology, PA, San Antonio, TX; Department of Medicine, Division of Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX; School of Pharmacy, University of Connecticut, Farmington, CT; and Sugen, Inc, Redwood City, CA. Address reprint requests to S. Gail Eckhardt, MD, Cancer Therapy and Research Center, 8122 Datapoint Dr, Suite 700, San Antonio, TX 78229; email geckhardt{at}saci.org
PURPOSE: To evaluate the clinical feasibility and pharmacologic behavior of the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor SU101, administered on a prolonged, intermittent dosing schedule to patients with advanced solid malignancies.
PATIENTS AND METHODS: Twenty-six patients were treated with SU101 doses ranging from 15 to 443 mg/m2 as a 24-hour continuous intravenous (IV) infusion weekly for 4 weeks, repeated every 6 weeks. Pharmacokinetic studies were performed to characterize the disposition of SU101 and its major active metabolite, SU0020. Immunohistochemical staining of PDGF-
RESULTS: Twenty-six patients were treated with 52 courses (187 infusions) of SU101. The most common toxicities were mild to moderate nausea, vomiting, and fever. Two patients experienced one episode each of grade 3 neutropenia at the 333 and 443 mg/m2 dose levels. Dose escalation of SU101 above 443 mg/m2/wk was precluded by the total volume of infusate required, 2.5 to 3.0 L. Individual plasma SU101 and SU0020 concentrations were described by a one-compartment model that incorporates both first-order formation and elimination of SU0020. SU101 was rapidly converted to SU0020, which exhibited a long elimination half-life averaging 19 ± 12 days. At the 443 mg/m2/wk dose level, trough plasma SU0020 concentrations during weeks 2 and 4 ranged from 54 to 522 µmol/L. Immunohistochemical studies revealed PDGF- CONCLUSION: SU101 was well tolerated as a 24-hour continuous IV infusion at doses of up to 443 mg/m2/wk for 4 consecutive weeks every 6 weeks. Although further dose escalation was precluded by infusate volume constraints, this SU101 dose schedule resulted in the achievement and maintenance of substantial plasma concentrations of the major metabolite, SU0020, for the entire treatment period.
SU101 (LEFLUNOMIDE; N-[4-(trifluoromethyl)phenyl]-5-isoxazole-4-carboxamide) is an isoxazole derivative that interferes with signal transduction by inhibiting platelet-derived growth factor (PDGF) receptor–mediated tyrosine phosphorylation, DNA synthesis, cell cycle progression, and cellular proliferation.1,2 PDGFs are a family of protein dimers that consist of A and B chains linked by disulfide bonds, comprising three isoforms, PDGF-AA, -AB, and -BB.3 The two PDGF receptors, alpha and beta, are members of the subclass III family of receptor tyrosine kinases, which are characterized by dimeric ligand binding and an immunoglobulin-like extracellular domain.4,5 The binding of PDGF to its receptor results in phosphorylation of tyrosine residues, which, in turn, conveys a series of growth-related signals to the nucleus. The transduced signals ultimately generate biologic effects, including cellular proliferation, differentiation, and migration.5,6 Several lines of evidence indicate that PDGFs are involved in malignant transformation. Early on, it was discovered that the gene encoding the PDGF B chain was the cellular homolog of the simian sarcoma virus v-sis oncogene, thus establishing an association between PDGF and a viral gene that induces oncogenic transformation.7,8 In glioblastoma cell lines, both PDGF and PDGF receptors are coexpressed, indicating an autocrine loop of tumor growth stimulation by PDGF and its receptors within the same tumor cell.9,10 In other human malignancies of pancreatic, breast, glial, and lung origin, immunohistochemical studies have also demonstrated both PDGF and PDGF receptors, which suggests that autocrine stimulation mediated by PDGF may be a common mechanism responsible for human tumor proliferation.11-14 In addition, PDGFs are potent mitogens and chemoattractants for both fibroblasts and endothelial cells, and they may also play a critical role in providing vascular and stromal support for tumor development.15-17
SU101 inhibits the transduction of proliferative signals that are mediated by the PDGF receptor. For example, treatment of C6 rat glioma cells with SU101 inhibits PDGF-mediated receptor phosphorylation in a dose-dependent manner without altering the level of receptor expression.1 Against a human glioma cell line that overexpresses the PDGF receptor, SU101 inhibited receptor phosphorylation with a median inhibitory concentration (IC50) value of 65 µmol/L, whereas it had a negligible effect (IC50, > 1,000 µmol/L) on cell lines that overexpress unrelated receptors, such as the epidermal growth factor receptor, insulin growth factor-1 receptor, or insulin receptor.1 SU101 has also been demonstrated to inhibit downstream nuclear processes, such as DNA synthesis and cell cycle progression. In murine 3T3 cells that overexpress the PDGF- The results of preclinical studies in animals also indicate that the antitumor activities of SU101 are principally related to inhibitory effects at the level of the PDGF receptor. In a series of experiments in which mice bearing human tumors implanted subcutaneously were treated daily with SU101 intraperitoneally (IP), significant tumor growth inhibition generally occurred in leukemia, glial, ovarian, melanoma, prostate, and lung xenografts that overexpress the PDGF-ß receptor.1 Significant growth-inhibitory effects were also noted when animals were treated with SU101 on less frequent schedules, such as IP administration every 2, 4, or 7 days.2 SU101 is converted in vivo to its major metabolite, SU0020 (N-[4-(trifluoromethyl)phenyl]-2-cyano-3-hydroxyl-2-butenamide) (Fig 1), by an intramolecular rearrangement. The conversion of SU101 to SU0020 occurs rapidly in the plasma of both rat and humans at 37°C, but the rate of conversion is substantially less in heat-inactivated plasma, suggesting that the process is mediated enzymatically.2 Recent evidence suggests that the mechanisms for the antiproliferative effects of SU101 and SU0020 are vastly different. Whereas the antitumor effects of SU101 are PDGF receptor–dependent, SU0020 has been shown to interfere with de novo pyrimidine synthesis via the enzyme dihydroorotate dehydrogenase.18-21 Thus, the administration of SU101 in vivo may result in both PDGF receptor–dependent and PDGF receptor–independent antiproliferative effects.
In preclinical toxicology studies, SU101 primarily affected rapidly proliferating tissues such as gastrointestinal, lymphoid, and hematopoietic tissues.2 In addition, there was histopathologic and laboratory evidence of erythropoiesis, reticulocytosis, and anemia, which suggested that SU101 and/or its excipient induces peripheral destruction of RBCs.2 The SU101 dose associated with lethality in 10% of treated rats (LD10) when SU101 was administered IV weekly for 4 consecutive weeks, 25 mg/kg (150 mg/m2), resulted in minimal toxicity in monkeys. In rats and monkeys, the elimination half-lives of SU0020 ranged from 10 to 17 and from 8 to 21 hours, respectively.2
The decision to pursue the clinical development of SU101 was based on the agent's novel mechanism of action as an inhibitor of PDGF receptor tyrosine kinase phosphorylation, as well as the broad spectrum of antitumor activity and favorable toxicity profile of SU101. A weekly administration schedule was selected because optimal biologic activity in preclinical studies appeared to be associated with greater total doses of SU101 administered on intermittent schedules. The principal objectives of this phase I and pharmacologic study of SU101 were to: (1) characterize the toxicities of SU101 administered as a 24-hour continuous IV infusion weekly for 4 weeks every 6 weeks in patients with advanced solid malignancies; (2) determine the maximum-tolerated dose (MTD) and recommended dose for subsequent phase II-III trials of SU101; (3) characterize the pharmacologic behavior of SU101 and of SU0020; (4) seek preliminary evidence of antitumor activity in patients with advanced cancers; and (5) evaluate PDGF-
Patient Selection Patients with histologically documented solid malignancies refractory to standard therapy or for whom no effective therapy existed were eligible for this study. Other relevant eligibility criteria included: (1) age at least 18 years; (2) Karnofsky performance status (KPS), at least 60%; (3) no chemotherapy or investigational agents within 4 weeks (6 weeks for nitrosoureas or mitomycin); (4) adequate hematopoietic (absolute neutrophil count,  1,500/µL; hemoglobin, 9.0 g/dL; platelet count, 100,000/µL), hepatic (total bilirubin,  1.5 times the upper limit of normal; AST, ALT, and alkaline phosphatase, 3.0 times the upper limit of normal), and renal (creatinine concentration, < 2.0 mg/dL) functions; (5) no known hypersensitivity to medications formulated in polysorbate 80; and (6) no coexisting medical problem of sufficient severity to limit full compliance with the study. Informed consent was obtained according to federal and institutional guidelines.
Drug Administration SU101 was supplied by Sugen, Inc. (Redwood City, Ca.), in 30-mL vials containing 60 mg of SU101 in 25 mL (2.4 mg/mL) of vehicle, consisting of dehydrated ethanol (12.6%), benzyl alcohol (1.5%), polysorbate 80 (4.0%), polyethylene glycol (32.5%), citric acid (0.3%), and water (52.2%). To prevent hemolysis, the total daily dose was diluted 1:7.5 with 5% dextrose:0.45% normal saline solution before administration. The final solution was stable for 36 hours at room temperature. Infusion bags and tubing were composed of nonpolyvinylchloride, nondiethylhexylphthalate materials, and an IMED programmable infusion pump (IMED Corp, San Diego, CA) was used to achieve a constant rate of infusion over 24 hours.
Pretreatment and Follow-Up Studies Evaluations of measurable or assessable disease were initially performed after each 6-week course, but the frequency of assessment was subsequently modified to evaluation after every other course. A complete response was defined as the disappearance of all disease documented by measurements separated by at least 4 weeks without worsening of disease-related symptoms or KPS, whereas a partial response required at least a 50% reduction in the sum of the bidimensional products of all measurable lesions documented by at least two measurements separated by at least 4 weeks. Patients were allowed to continue treatment in the absence of disease progression or intolerable toxicity.
Pharmacokinetic Sampling and Assay SU101 and SU0020 concentrations were measured by high-performance liquid chromatography in our laboratory. Analytic standards were provided by Sugen, Inc. Before quantitation, the samples were thawed on ice and a 200-µL aliquot was transferred to a 5-mL polypropylene tube. Twenty-five microliters of internal standard (SU0070; 5-methylpyrazole-4-carboxylic acid-4-trifluoromethylanilide) was added to the sample, followed by 7.5 µL of 1.0 M HCl. Both SU101 and SU0020 were extracted using 1.5 mL of acetonitrile. After centrifugation, the supernatant was transferred to a clean polypropylene tube and evaporated to dryness in a Savant SC100 SpeedVac (Holbrook, NY) which was set to medium. The temperature of the chamber did not exceed 45°C. Extracts were reconstituted in 100 µL of methanol:mobile phase (75:25) for analysis. The high-performance liquid chromatography system consisted of a Waters 510 isocratic solvent delivery pump (Waters Corp, Milford, PA), a Waters 717-plus refrigerated autosampler, and a Waters model 441 fixed-wavelength absorbance detector. Data were collected using Waters Maxima chromatography data collection software. The mobile phase consisted of 0.35 M potassium phosphate (pH 4.5), methanol, and water in a ratio of 45:550:405. Triethylamine was added to a final concentration of 0.6%. The mobile phase was filtered through a 0.45-µM filter and degassed in an ultrasonicator before use. After injection of a 15-µL sample, the compounds were separated using a 5-µM, 100-mm x 4.6-mm ODS Hypersil column (Hewlett Packard, Wilmington, DE), maintained at 40°C with a Waters column temperature control system. Detection was at 254 nm, and the flow rate was 1.2 mL/min. The retention times for SU101, SU0020, and the internal standard (SU0070) were 6.25, 2.05, and 4.11 minutes, respectively. During chromatographic analysis, reconstituted samples were maintained at 4°C in the autosampler.
Drug concentrations were calculated from calibration curves made with pretreatment plasma from each subject at SU101 and SU0020 concentrations that ranged from 0.5 to 200 µg/mL. Unknown concentrations of SU101 and SU0020 were determined using linear least-squares regression with a weighting factor of 1/x. Calibration curves were linear from 0.500 to 400 µg/mL for both SU101 and SU0020 (r2
Pharmacokinetic Analysis
The model was characterized by the following structural parameters: volume of distribution of SU101 (VSU101), volume of distribution of SU0020 (VSU0020), rate constant for the formation of SU0020 from SU101 (Kf), and rate constant for elimination of SU0020 from plasma (Ke). VSU101 was estimated if there were sufficient concentration data available. A model that incorporated two-compartmental disposition for SU0020 was also evaluated. Discrimination between pharmacokinetic models was guided graphically and numerically using the values of the objective function and the log-likelihood difference. The lack of statistical improvement in predicted plasma concentrations precluded the use of a model incorporating two-compartmental SU0020 disposition in all but four patients. Model structural parameters were estimated using the nonlinear mixed-effects modeling program (NONMEM; NONMEM Project Group, UCSF, San Francisco, CA), which uses an extended least-squares algorithm. Residual error for all fitting was modeled as combination error, which included both additive and proportional components. This residual-error model accounted for sample timing errors, model misspecification error, assay error, and biologic noise. The following pharmacokinetic parameters were calculated from the model: the elimination half-lives of SU101 (t1/2,SU101) and SU0020 (t1/2,SU0020), the distributive volume of SU0020 (VSU0020), and the clearance of SU0020 (ClSU0020).
Immunohistochemistry
Twenty-six patients received 52 total courses (187 infusions) of SU101 at doses ranging from 15 to 443 mg/m2/wk for 4 consecutive weeks every 6 weeks. All patients were assessable for toxicity. Patient characteristics are listed in Table 1. Twenty-four of the 26 patients had previously received chemotherapy, radiotherapy, or both. The dose escalation scheme, as well as the number of patients and courses administered as a function of dose level, is listed in Table 2. Only one patient required dose reduction from 443 to 333 mg/m2/wk, owing to grade 3 neutropenia at the higher dose. At least three new patients were treated at each dose level except for the 225 mg/m2 dose level, in which only a single patient was enrolled, because of the availability of sufficient safety data from a phase I trial of SU101 in patients with malignant glioma at another institution that was conducted in parallel with this trial. The median number of courses (four infusions) administered per patient was one (range, one to 13), and the median number of infusions administered was four (range, two to 52).
Toxicities Despite concerns raised in the preclinical toxicology studies, there was no clinical or laboratory evidence of drug- or excipient-induced hemolysis. Two patients also developed grade 3 hematologic toxicity. One patient, a 57-year-old male with advanced hormone-refractory prostate cancer whose immediate prior therapy consisted of estramustine phosphate within 23 days of SU101, experienced grade 3 neutropenia during the third week of his first course at the 333 mg/m2 dose level, which delayed his scheduled fourth treatment by 1 week. The second patient, a 34-year-old male with an anaplastic astrocytoma and extensive prior myelosuppressive therapy, developed grade 3 neutropenia during his second course of SU101 at the 443 mg/m2 dose level. His dose was subsequently reduced to 333 mg/m2, which consistently resulted in either grade 1 or 2 neutropenia and grade 1 thrombocytopenia during each of 11 subsequent courses.
Antitumor Activity
Pharmacokinetic Studies
Pharmacokinetic parameter estimates for patients treated with SU101 at all nine dose levels are listed in Table 3. The mean t1/2,SU101 was 1.8 (CV, 106%) hours. In contrast, the clearance rate of SU0020 was profoundly slow, averaging 0.42 L/d/m2 (CV, 66%), and t1/2,SU0020 averaged 19 days (CV, 62%). VSU0020 averaged 7.9 L/m2 (CV, 20%). The relationship between trough plasma SU0020 concentrations measured before treatment during weeks 2 and 4 correlated with the dose of SU101, as shown in Fig 3 (r2, 0.69 and 0.57, respectively). At the maximum-feasible dose, 443 mg/m2, mean trough (± SD) concentrations during weeks 2 and 4 were 119 (± 71) µmol/L and 302 (± 193) µmol/L, respectively. At the 225 to 443 mg/m2 dose levels, trough plasma SU0020 concentrations during week 2 (range, 54 to 195 µmol/L) and week 4 (range, 137 to 522 µmol/L) consistently exceeded SU0020 concentrations (5 to 30 µmol/L) that significantly inhibit the proliferation of cells in vitro.18-21
Immunohistochemistry
The transduction of proliferative signals mediated by extracellular membrane receptors for growth factors such as PDGF, epidermal growth factor, and vascular endothelial growth factor is an attractive target for therapeutic intervention in cancer. This notion is further supported by preclinical studies, which have demonstrated that these ligands and their receptors are closely associated with malignant transformation and proliferation.3,6 SU101, an inhibitor of PDGF receptor tyrosine phosphorylation, blocks the transduction of proliferative signals mediated by the PDGF receptor in a dose-dependent manner, thereby inhibiting DNA synthesis and cell cycle progression.1 In preclinical studies, SU101 demonstrated notable antitumor activity against neoplasms that overexpress the PDGF receptor, as well as a predictable and favorable toxicologic profile.1,2 This phase I and pharmacologic study was designed to evaluate the feasibility of administering SU101 as a 24-hour continuous IV infusion weekly for 4 weeks every 6 weeks, which was projected to result in prolonged exposure to biologically relevant concentrations of SU101 and its metabolite, SU0020. The toxicities associated with SU101 on this administration schedule, even at the maximum-feasible dose of 443 mg/m2, were tolerable over the entire dosing range. The most common adverse effects were mild to moderate nausea and vomiting, which were managed successfully with antiemetics. In fact, premedication with antiemetics was required in only one patient. Although two individuals developed grade 3 neutropenia that required either treatment delay or dosage reduction, neither gastrointestinal nor hematologic effects precluded the repetitive administration of SU101 on this treatment schedule. Other mild to moderate drug-related toxicities included fever in the peritreatment period, which occasionally required treatment with antipyretics, and phlebitis in 13% of SU101 infusions that were administered through a peripheral vein. No patient experienced DLT or toxicities that consistently resulted in treatment delay or dosage reduction. Instead, the administration of SU101 at doses above 443 mg/m2 was precluded by the large volume of infusate required for dilution and administration of the SU101 formulation used in this study. Treatment with SU101 at its maximum-feasible dose, 443 mg/m2, required a minimum infusate volume of 2.6 L for a body-surface area of 1.8 mg/m2, whereas treatment at the next higher dose level of 589 mg/m2 would have required a minimum infusate volume of 3.3 L. Although this trial did not define an MTD for SU101 on this schedule using conventional toxicity criteria, the present study established a well-tolerated dose schedule in which substantial concentrations of the major metabolite were sustained for prolonged periods. In contrast to the principal objective in phase I studies of classic cytotoxic agents in which the recommended phase II dose is the MTD, phase I studies of agents such as SU101 that mediate antitumor activity via "antiproliferative" means and require protracted administration must determine doses that result in pharmacologic conditions required for optimal activity and are amenable to prolonged administration. However, the ideal dose derived from a phase I trial should be based on a constellation of factors that include toxicity, pharmacology, and clinical feasibility. Therefore, based on the available toxicologic and pharmacologic results of this trial, and in light of preclinical studies of SU101 and SU0020, 443 mg/m2 is an appropriate dose for subsequent evaluations of SU101 on this schedule. The current formulation of SU101 has been modified to permit the administration of this dose over 4 to 6 hours, thus enhancing the clinical feasibility of this schedule. This study sought to characterize the pharmacologic profiles of SU101 and SU0020, particularly to determine whether pharmacologic conditions associated with significant inhibition of PDGF receptor tyrosine kinase activity and tumor growth inhibition could be achieved in patients with advanced malignancies. To accomplish this objective, a pharmacokinetic model was derived in which first-dose concentration data were described and then used to predict SU0020 concentrations achieved over multiple courses. The disposition of SU101 in plasma was best described by a one-compartment linear model that incorporates first-order formation and elimination of SU0020. Although there were limited plasma SU101 concentration-time data available owing to the rapid molecular rearrangement of SU101 to SU0020, the model enabled determination of SU0020 formation (Kf) and elimination (Ke) rate constants and estimates of secondary pharmacokinetic parameters in nearly all patients. A two-compartment model of the disposition of SU101 and the formation of SU0020 in plasma was also evaluated, but the model was less satisfactory than the one-compartment model. The two-compartment model offered no improvement in the prediction of observed concentrations, even in the four subjects who had sufficient SU101 concentration-time data available. The pharmacokinetics of SU101 and SU0020 were linear over the range of doses evaluated in the present study. Mean (± SD) pharmacokinetic parameters included a t1/2,SU101 of 1.77 (± 1.88) hours, VSU0020 of 7.9 (± 1.5) L/m2, t1/2,SU0020 of 19 (± 12) days, and ClSU0020 of 0.42 (± 0.28) L/d/m2. The magnitude of VSU0020 suggests that the metabolite distributes predominantly within the intravascular compartment. Surprisingly, the clearance of SU0020 in humans was much slower compared with the clearance rates observed in animals. In rats and monkeys, t1/2,SU0020 values ranged from 10 to 17 hours and from 8 to 10 hours, respectively.2 One explanation for these interspecies differences, as well as the slow clearance rate of SU0020 in human plasma, is its extent (> 99%) of binding to plasma proteins. For example, the preferential binding of SU0020 to human plasma albumin, which has an average clearance rate of 25 days, may account, in part, for the low clearance rate of SU0020. Additionally, interspecies differences in the avidity of SU0020 binding to erythrocytes or other blood components may contribute to the differences in clearance rates. Owing to the limitations of the sensitivity of the analytic assay, as well as the intrinsic metabolic and rapid initial distributive characteristics of SU101, the pharmacokinetics of the parent compound could not be sufficiently described, nor was it possible to relate the magnitude of SU101 plasma concentrations achieved in this study to SU101 concentrations associated with PDGF receptor–mediated biologic activity in vitro. In contrast, the magnitude of SU0020 concentrations achieved in plasma could be related to those associated with biologic activity in preclinical studies; trough SU0020 concentrations at the 225 to 443 mg/m2 dose levels during weeks 2 (range, 54 to 195 µmol/L) and 4 (range, 137 to 522 µmol/L) exceeded SU0020 concentrations that are known to inhibit the growth of cells in vitro, albeit most likely by PDGF-independent mechanisms (eg, inhibition of pyrimidine biosynthesis).18-21 Although the preponderance of SU0020 in plasma greatly complicates efforts directed at determining the precise contributions of PDGF-dependent and PDGF-independent mechanisms to the overall antiproliferative effects of SU101, it does not indicate that SU101 is devoid of PDGF-dependent activity in vivo. For drugs such as SU101, which are widely and avidly distributed to peripheral tissues and consequently possess large Vd values, the plasma compartment may not adequately reflect the behavior of the agent in the peripheral tissue compartment. This discrepancy is illustrated by the fact that, despite undetectable concentrations of SU101 in plasma after parenteral IP administration to rats bearing C6 glioma, SU101 was the predominant chemical species detected intratumorally.22 In addition, the prevailing chemical species, and hence the principal mechanism responsible for the activity of SU101 in vivo, may be related to the specific dose and route of SU101 administration.22 An oral form of SU101 (leflunomide; Hoechst, AG) is currently being evaluated in patients with rheumatoid arthritis, psoriasis, and systemic lupus erythematosus at doses (25 mg/d) that are substantially lower than those evaluated in the present study, and SU0020 has been the only chemical species identified in the plasma.23 Furthermore, the oral administration of SU101 in rats bearing C6 PDGF-expressing glioma results in tumor growth inhibition that is abrogated if both uridine and SU101 are administered together, indicating that PDGF-independent mechanisms are operative when SU101 is administered in this manner.22 Nevertheless, the principal mechanism by which SU101 may induce antitumor activity in vivo, as well as the relative contributions of PDGF-dependent and PDGF-independent mechanisms, cannot be discerned at present. In any case, regardless of the outcome of subsequent disease-directed phase II and III trials of SU101, it will be necessary to ascertain information about the relative contributions of PDGF-dependent and PDGF-independent mechanisms to the overall antitumor actions of SU101 in vivo to optimize the development of anticancer therapeutics that specifically target these mechanisms.
The development of SU101 and other inhibitors of proliferative signal transduction present unique challenges with regard to clinical trial design. One dilemma that was encountered in designing the present study, which will undoubtedly be revisited in evaluations of other inhibitors of signal transduction, is whether or not to restrict eligibility to patients with malignancies that are presumed to overexpress the receptor target. However, if such restrictions had been incorporated into the design of this study from the outset, several patients whose tumors were demonstrated retrospectively to overexpress PDGF- The results of this phase I and pharmacologic study indicate that treatment with SU101 as a 24-hour IV infusion weekly for 4 weeks every 6 weeks is associated with minimal adverse effects at doses that achieve biologically relevant (irrespective of the predominant mechanism for these effects) plasma drug concentrations for protracted periods. In essence, these toxicologic and pharmacologic results are precisely those that must be accomplished before beginning broad disease-directed efficacy evaluations with SU101 and other agents that induce antitumor activity largely by antiproliferative mechanisms. With regard to the appropriate design of subsequent efficacy studies, although such agents may indeed induce cytoreduction in the classic sense, it is more likely that cytostasis will be the predominant effect of these agents, which may not be adequately appreciated in nonrandomized, classic phase II studies. Instead, randomized trials will likely be required to discern the effects of cytostasis on more appropriate clinical end points such as time to tumor progression, quality of life, symptomatic improvement, and survival. For those growth-inhibitory agents that exert maximal inhibitory effects on tumor growth in combination with classic cytotoxic agents, an appropriate study might involve randomization of patients to treatment with the cytotoxic agent in combination with the tumor growth-inhibitory agent or placebo. Finally, the optimal clinical setting in which to evaluate such cytostatic agents may be in patients with minimal residual disease after surgery, radiation, or adjuvant chemotherapy. Nevertheless, in addition to defining the principal mechanism responsible for the effects of SU101 in vivo, it is clear that the optimal clinical development of this agent will require the use of novel trial designs and strategies, perhaps involving patients with high-grade astrocytoma and other neoplasms in which aberrant cellular proliferation is primarily mediated by PDGF-dependent pathways, although targeting malignancies whose growth might be independent of PDGF-related mechanisms should also be considered.
This article is dedicated to the memory of Maura Kraynak, whose commitment to work and patient care will be forever remembered.
Deceased. This work was supported in part by a grant from Sugen, Inc.
1. Shawver L, Schwartz DP, Mann E, et al: Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-(trifluoromethyl)phenyl]-5-methylisoxazole-4-carboxamide. Clin Cancer Res 3:1167-1177, 1997[Abstract] 2. SU101 [Clinical Investigator's Brochure]. Redwood City, CA, Sugen, Inc, 1998
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Doolittle RF, Hunkapiller MW, Hood LE, et al: Simian sarcoma virus oncogene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221:275-277, 1983 8. Waterfield MD, Scrace GT, Whittle N, et al: Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature 304:35-39, 1983[Medline]
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Antoniades HN, Galanopoulos T, Neville-Golden J, et al: Malignant epithelial cells in primary human lung carcinomas coexpress in vivo platelet-derived growth factor (PDGF) and PDGF receptor mRNAs and their protein products. Proc Natl Acad Sci USA 89:3942-3946, 1992 15. Brouty-Boye D, Magnien V: Myofibroblast and concurrent ED-beta fibronectin phenotype in human stromal cells cultured from non-malignant and malignant breast tissue. Eur J Cancer 30A:66-73, 1994 16. Ponten F, Ren Z, Nister M, et al: Epithelial-stromal interactions in basal cell cancer: The PDGF system. Invest Dermatol 102:304-309, 1994[Medline]
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Forsberg K, Valyi-Nagy I, Heldin CH, et al: Platelet-derived growth factor (PDGF) in oncogenesis: Development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. Proc Natl Acad Sci USA 90:393-397, 1993 18. Nair RV, Cao W, Morris RE: Inhibition of smooth muscle cell proliferation in vitro by leflunomide, a new immunosuppressant, is antagonized by uridine. Immunol Lett 47:171-174, 1995[Medline] 19. Greene S, Watanabe K, Braatz-Trulson J, et al: Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. Biochem Pharmacol 50:861-867, 1995[Medline] 20. Williamson RA, Yea CM, Robson PA, et al: Dihydroorotate dehydrogenase is a target for the biological effects of leflunomide. Transplant Proc 28:3088-3091, 1996[Medline] 21. Xu X, Williams JW, Gong H, et al: Two activities of the immunosuppressive metabolite of leflunomide: Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation. Biochem Pharmacol 52:527-534, 1996[Medline] 22. Shawver LK, Sutton B, West KA, et al: The antitumor efficacy of SU101 in human tumor models is exerted by the parent compound and not the metabolite. Proc Am Assoc Cancer Res 39:2185, 1998 (abstr) 23. Mladenovic V, Domljan Z, Rozman B, et al: Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis: Results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 38:1595-1603, 1995[Medline] Submitted May 18, 1998; accepted December 21, 1998. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
and -ß receptors was performed on malignant tumor specimens obtained at diagnosis. 
, observed concentrations; ——, best-fit curve using modeled parameters.
, week 4.
