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Journal of Clinical Oncology, Vol 21, Issue 2 (January), 2003: 232-240
© 2003 American Society for Clinical Oncology

SarCNU, a Nitrosourea Analog on a Day 1, 5, and 9 Oral Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Tumors

L. Panasci, S.F. Stinson, D. Melnychuk, V. Sandor, W.H. Miller, Jr, G. Batist, F. Patenaude, N. Bangash, L. Panarello, M. Alaoui-Jamali, E. Sausville

From the McGill Center for Translational Research in Cancer, Jewish General Hospital, Montreal, Quebec, Canada; and National Cancer Institute, Developmental Therapeutics Program, Bethesda, MD.

Address reprint requests to L. Panasci, MD, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec, H3T 1E2, Canada; email: lpanasci{at}hotmail.com.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a novel chloroethylnitrosourea that demonstrates selective cytotoxicity in athymic mice bearing human glioma. SarCNU demonstrates selective cytotoxicity in vitro against human glioma at least in part because of the selective SarCNU uptake by the extraneuronal monoamine transporter. The purpose of this phase I study was to determine the maximum-tolerated dose (MTD), the toxicity profile, the pharmacokinetics profile, and recommended phase II dose.

Patients and Methods: Forty-three eligible patients with advanced solid tumors were enrolled. SarCNU was administered orally on days 1,5, and 9 every 28 days. The dose ranged from 30 to 1,075 mg/m2. Pharmacokinetic evaluation was done on the first cycle (one dose was given intravenously on day 1 or 5 of the first cycle to determine bioavailability).

Results: Delayed myelosuppression (thrombocytopenia and neutropenia occurring 4 to 6 weeks after administration) was the dose-limiting toxicity (DLT). Anemia occurred but was mild. Nonhematologic toxicity was generally mild, but one patient died with pulmonary toxicity that was probably secondary to SarCNU. There were no partial or complete responses, but eight patients had stable disease for 19 to 46 weeks. The oral bioavailability of SarCNU was 80% ± 37%. The terminal phase half-life was similar after intravenous (58.4 ± 23.5 minutes) or oral (64.0 ± 34.8 minutes) administration. The total plasma clearance was 20.4 ± 8.8 L/h/m2, and the apparent volume of distribution was 29.9 ± 17.6 L/m2. The area under the plasma concentration–time profile increased proportionally with the dose, and the pharmacokinetics seemed to be independent of the route of administration and the number of doses.

Conclusion: SarCNU was well tolerated and the MTD was 1,075 mg/m2. The recommended starting dose for phase II trials is 860 mg/m2 orally on days 1, 5, and 9 every 6 weeks.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
SARCNU (2-CHLOROETHYL-3-SARCOSINAMIDE-1-NITROSOUREA) is a novel analog of the chloroethylnitrosoureas, which does not form an organic isocyanate because the N-3 position is blocked with a methyl group (Fig 1Go). Thus, the decomposition of this compound is unique in this class of agents. The carrier group is a methylglycinamide, which is an amino acid amide. The compound was originally synthesized with the impression that the carrier group would allow for transport by the amino acid transporters.1



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  		Fig 1. Structure of 2-chloroethyl-3-sarcosinamide-1-nitrosourea.

 
SarCNU was compared to carmustine (BiCNU) in the human tumor cloning assay using primary glioma specimens from patients. At its predicted peak plasma concentration (15 µg/mL), SarCNU was highly superior to BiCNU in suppressing tumor growth in vitro. Moreover, SarCNU was less myelotoxic than BiCNU in the in vitro colony-forming unit culture assay.2,3 All clinically available CNUs enter tumor cells via passive diffusion.4 SarCNU is unique in that the presence of the sarcosinamide carrier group allows the group to enter cells via the extraneuronal monoamine transporter. This transporter accounts for the increased intracellular accumulation of SarCNU in the SK-MG-1 glioma cell line and contributes to its enhanced cytotoxicity.5–7 The selective cytotoxicity of SarCNU is at least in part caused by the extraneuronal monoamine transporter because a human glioma cell line, SKI-1, which has no detectable transporter, accumulates less SarCNU and is less sensitive to SarCNU as compared to SK-MG-1 cells.5 SarCNU is representative of a potentially new class of anticancer agents that displays increased antitumor activity by exploiting a physiologic aspect of the tumor cell. SarCNU at its maximum-tolerated dose (MTD; both intravenous [IV] and oral [PO] administered) resulted in the majority of athymic mice bearing SF-295 central nervous system tumors being long-term, tumor-free survivors, whereas BiCNU at its MTD produced no tumor-free animals. Furthermore, SarCNU at lower doses retained high tumor activity. There may be a significant relationship between the dosing schedule of SarCNU and its efficacy. Although a single dose of SarCNU produced no tumor-free animals, multiple daily doses did result in a high percentage of tumor-free animals.8 This may be caused by a kinetic advantage for SarCNU accumulation associated with multiple dosing. In addition, the PO route was more efficacious.

The toxicology profile of IV or PO SarCNU has been evaluated in mice, rats, and dogs and compared to BiCNU.9,10 In general, the toxicology profile of SarCNU was similar to IV BiCNU, but the MTD of SarCNU was approximately fivefold greater than that of BiCNU. At the MTD, SarCNU in rats resulted in myelotoxicity, including neutropenia, thrombocytopenia, and to a lesser extent, anemia 8 to 43 days after administration. There was evidence of pulmonary toxicity in rats that is similar to that of BiCNU.

Because of the improved therapeutic index of PO SarCNU, oral bioavailability studies were performed in rats and dogs. The mean bioavailability in rats was 65% to 96%, and it was 73% in dogs. The t1/2 following IV or PO SarCNU at various doses was 22 to 59 minutes.

In view of the above-mentioned studies, a phase I trial of SarCNU was done to (1) determine the MTD and recommended doses for phase II trials of PO SarCNU given on days 1, 5, and 9 every 28 days; (2) determine bioavailability (IV SarCNU was given on day 1 or 5 of the first cycle); (3) determine the pharmacokinetics of SarCNU; (4) characterize the toxicities associated with SarCNU given on this schedule; and (5) seek any evidence of antitumor activity that may occur.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility
Patients with histologically or cytologically proven solid tumors that were refractory to standard therapy or for which there was no effective therapy were eligible. It was preferable that patients had measurable or assessable lesions. Eligibility criteria included the following: >= 18 years old, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, life expectancy of greater than 3 months, and adequate organ function (ie, hemoglobin more than 8 g/dL, WBC count >= 4,000/µL, neutrophil count >= 1,500/µL, platelet count >= 120,000/µL, total bilirubin level < 1.5 mg/dL, AST and ALT levels < 2.5 times upper normal limits, serum creatinine < 1.5 mg/dL or creatinine clearance > 60 mL/min) were required. At least 4 weeks (6 weeks in the case of nitrosourea, mitomycin, and radiation therapy to more than 20% of all the bones in the body) must have elapsed since the completion of previous therapy. In addition, patients must have recovered from the toxic effects of the previous therapy. Exclusion criteria included heart failure, uncontrolled infection, uncontrollable diabetes mellitus, myelodysplastic syndrome, human immunodeficiency virus infection, brain metastases, pregnancy, lactation, and recent surgery. The medical ethics committee of the hospital approved the study, and all patients gave written informed consent.

Pretreatment and Follow-Up Studies
Before study entry, a complete history and physical examination including height, weight, body surface area, ECOG performance status, and clinical stage were performed. Pretreatment laboratory data included a complete blood cell count, chemistry profile, electrolytes determination, and urinalysis. These laboratory studies (except urinalysis) were repeated on days 5 and 9 and weekly thereafter. A chest x-ray and electrocardiogram were performed before treatment and, if possible, at the end of each course. Toxicities were evaluated according to the National Cancer Institute common toxicity criteria. Tumor responses were assessed by standard response criteria. A complete response required the complete disappearance of all clinical evidence of disease for at least 4 weeks, with no evidence of new areas of malignant disease. A partial response required a >= 50% decrease in the sum of the products of the perpendicular diameters of all measured lesions that persisted for at least 4 weeks, with no new lesions appearing. A minor response required a decrease in the sum of the products of the perpendicular diameters of all measured lesions of 25% to 50%. Progressive disease (PD) was defined as any increase of more than 25% in the products of the perpendicular diameters of any measured lesions or the appearance of a new lesion on any imaging study. The remaining patients who did not meet any of these criteria were categorized as exhibiting no change. Response duration was calculated as the time from the first documentation of major response to the first documentation of PD.

Drug Administration and Dose Escalation
SarCNU was administered PO (capsules of 25 or 100 mg) or IV in 100 mL of 0.9% saline over 1 hour on days 1, 5, and 9 (either day 1 or 5 was IV). Therapy was repeated every 28 days. The starting dose was 30 mg/m2, which is one tenth of the lethal dose for 10% of rats. Three patients were entered at each dose level; there were 12 subsequent dose escalations from 30 to 1,075 mg/m2 at each dose level. Three additional patients were entered at the same dose if the DLT was observed in one of the first three patients. The MTD was defined as the dose at which two of three patients experienced DLT. The definition of DLT was as follows: grade 4 neutropenia lasting at least 3 days or grade 4 neutropenia associated with fever, or grade 4 thrombocytopenia according to National Cancer Institute common toxicity criteria. Intrapatient dose escalation was not allowed.

Patients with obvious evidence of PD were withdrawn from the study. For patients receiving more than one course of treatment, subsequent courses were started after complete recovery from the toxic effects of the previous course. All patients received ondansetron 4 mg PO 30 minutes before SarCNU administration.

SarCNU was supplied by the National Cancer Institute in vials containing 50 mg of lyophilized drug or in capsules containing 25 or 100 mg. The phase I trial was approved by the United States Food and Drug Administration and Therapeutics Products Programme (TPP) (Canada). The trial was performed at the McGill Center for Translational Research in Cancer at the Jewish General Hospital, Montreal, Canada.

Pharmacokinetic Sampling and Assay
Blood samples were collected to investigate the pharmacokinetic behavior and oral bioavailability of SarCNU after treatments on days 1, 5, and 9 of the first cycle. For the IV studies, samples were taken at 15, 30, and 45 minutes during the infusion; at the end of the infusion; and at 5, 10, 15, 30, 60, and 90 minutes and 2, 3, 4, and 6 hours after the end of the infusion. Following the first PO dose (day 5 or 1), samples were collected after 15, 30, 60, and 90 minutes and 2, 3, 4, and 6 hours. Following the second PO dose (day 9), samples were collected after 30 and 60 minutes and 2 hours. The actual IV dose received by the patient was less than the PO dose because a small percentage of the IV drug remained in the tubing and the actual dose received was calculated by subtracting this residual.

Blood samples were drawn into heparinized tubes. Plasma was separated by centrifugation and was analyzed by reversed-phase, high-performance liquid chromatography with ultraviolet detection using the method of Supko et al.11,12 Standard calibration curves were prepared over a concentration range of 0.1 to 52.8 µg/mL by the addition of known amounts of SarCNU and internal standard to appropriate volumes of human plasma. Linear, least squares regression analysis of SarCNU and internal standard chromatographic peak height ratio versus concentration data was used to determine the slope and y-intercept of the line of best fit. Concentrations of SarCNU in unknown plasma samples were determined by interpolation from the regression line. Samples were assayed in triplicate; the average of the closest two values was used for pharmacokinetic analysis.

Pharmacokinetic and Pharmacodynamic Analysis
SarCNU plasma concentration–time data from individual patients were analyzed by noncompartmental methods.13 Iterative, nonlinear, least squares regression analysis was performed using the software package Tablecurve (Jandel Scientific, San Rafael, CA). The slopes and intercepts of the individual regression lines were the iterated primary parameters. The line of best fit was determined by a consideration of the SEs of the fit and of the individual parameters and by analysis of residuals. Secondary pharmacokinetic parameters were calculated from the primary parameters by standard equations.13,14 For oral studies, the area under the plasma profiles from time zero to infinity (AUC) was calculated by linear trapezoidal rule to the last time point, with extrapolation to infinity accomplished by dividing the last measured concentration by the terminal phase rate constant. The maximum plasma concentration (Cmax) and the time to the Cmax (Tmax) were determined by inspection of the data.

Statistical Considerations
Parametric statistical tests were performed following logarithmic transformation of the data15,16 to ascertain whether the pharmacokinetics of SarCNU were dose or time dependent. Linear regression analysis was employed to investigate the dependence of the AUC and Cmax on the SarCNU dose. In addition, linear regression as well as nonlinear regression analysis using the sigmoidal maximum effect (Emax) model were used to examine the relationships between certain pharmacokinetic parameters and the maximum percentage change in platelet counts relative to pretreatment values. The a priori level for statistical significance was set at .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
General
Forty-three patients were entered on this phase I trial. They received a total of 110 courses. Their characteristics are shown in Table 1Go.


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  		Table 1. Patient Characteristics
 
Patients were initially treated with SarCNU at 30 mg/m2 PO on days 1, 5, and 9 every 28 days (one IV dose on day 1 or 5 to allow for comparative pharmacokinetics to determine oral bioavailability). Significant myelotoxicity was detected at the 550 mg/m2 dose level.

Myelotoxicity
After the first cycle of SarCNU, significant myelosuppression with both neutrophil nadirs and platelet nadirs was detected at days 36 to 50 and days 27 to 36, respectively (Table 2AGo). This pattern of myelosuppression is typical for the chloroethylnitrosoureas. It does not appear to be the case that myelosuppression was more severe with repeated doses of SarCNU (Table 2BGo). DLT was seen in the two patients treated at the dose of 1,075 mg/m2. Both patients had prolonged myelosuppression, and no additional patients were treated at this dose level. DLT was also seen in two patients treated at the 860-mg/m2 dose level. Both patients had been previously treated with chemotherapy and were older than 70 years of age. Furthermore, one of these two patients had received external beam radiotherapy to the pelvis followed 1 year later by brachytherapy to the pelvis. Anemia related to SarCNU was generally mild (grade 1) or moderate (grade 2) and cumulative, in that it tended to progressively worsen with repetitive dosing. Severe (grade 3) anemia, possibly related to drug and requiring red blood cell transfusions, was rare.


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  		Table 2. Hematologic Toxicity per Dose Level (worst per patient)
 
Nonhematologic Toxicity
Nausea and vomiting were rarely encountered. One patient at the 860-mg/m2 dose level forgot to take the prechemotherapy ondansetron and vomited following that dose. Alopecia was not detected. Mild (grade 1 to 2) complaints of dizziness and fatigue plus elevations in hepatic transaminases were noted (Table 3Go). These side effects were not greater with repeated doses of SarCNU, with the exception of dyspnea (Table 3BGo).


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  		Table 3. Nonhematologic Toxicities Observed
 
A patient with a glioblastoma multiforme, who had received a full course (60 Gy) of radiotherapy to the brain 3 months before starting SarCNU, was treated with five cycles of SarCNU at 690 mg/m2 (total dose 10,350 mg/m2 [21,000 mg]), and then developed dyspnea and died with pulmonary failure. Autopsy revealed lung changes consistent with drug-induced pulmonary toxicity. He had not received any other chemotherapy agents, and his concomitant medicines were dexamethasone 4 mg PO qid, clobazam 10 mg PO at bedtime, carbamazepine 400 mg PO qid, docusate 200 mg PO at bedtime, and sennosides two tablets daily. Six other patients had grade 2 to 3 dyspnea. These patients had lung or pleural metastases without any decreases in the carbon monoxide diffusion capacity in the lung or forced vital capacity. Of these six patients, one patient received six cycles of 690 mg/m2 (total dose 12,420 mg/m2 [20,700 mg]) and the other patients each received <= 3,225 mg/m2.

Pharmacokinetic Studies
Pharmacokinetic and bioavailability evaluations were conducted on plasma concentration–time data from 34 of the 35 patients given SarCNU by IV and PO routes. Data from an additional eight patients treated only by the PO route were also evaluated. Mean values of the pharmacokinetic parameters derived from nonlinear regression analysis of the data from oral studies are summarized in Table 4Go, and those from the IV studies are summarized in Table 5Go.


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  		Table 4. Pharmacokinetic Parameters for 2-Chlorethyl-3-sariosinamide-1-Nitrosourea Following PO Administration
 

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  		Table 5. Pharmacokinetic Parameters for 2-Chlorethyl-3-Sariosinamide-1-Nitrousourea Following Intravenous Administration
 
Following IV administration at doses of 324 mg/m2 or less, plasma concentrations of SarCNU decreased in a distinctly biexponential manner in all patients. At doses of 407 mg/m2 or above, however, plasma levels from eight of the 13 patients exhibited monoexponential decline. Representative plasma concentration–time profiles illustrating these patterns of disposition are shown in Fig 2Go, along with corresponding profiles from the oral studies in the same patients. After PO administration of SarCNU, plasma concentrations increased rapidly. The mean Tmax was 71.8 minutes (range, 15 to 180 minutes; coefficient of variation [CV], 60%). The mean terminal disposition phase half-life (t1/2,z) was similar after IV (58.4 ± 23.5 minutes) or PO (64.0 ± 34.8 minutes) administration. In addition, linear regression analysis revealed a significant correlation between t1/2,z values observed for individual patients after IV or PO treatment (R2 = 0.48, P < .001). The mean oral bioavailability (F) was 80% (CV, 46%).



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  		Fig 2. Representative 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) plasma concentration-time profiles demonstration biexponential (A) and monoexponential (B) disposition after IV administration, from two patients who received intravenous (•) and oral ({circ}) SarCNU. Points are the observed SarCNU plasma concentrations, and the lines are the best-fit curves determined by nonlinear regression analysis.

 
Regression analysis of body weight (mean, 70.8 ± 13.6 kg), or of body surface area (mean, 1.78 ± 0.20 m2) versus plasma clearance rate (CL), CL/F, and volume of distribution (V), indicated no significant relationship between body size and SarCNU CL or its apparent V within the range of body sizes encountered in this study. These pharmacokinetic parameters, therefore, were not normalized for body size.

The AUC and the Cmax increased proportionally with the dose following both IV and PO administration. Scatterplots demonstrating the relationship of CL and CL/F to dose are shown in Fig 3Go. There were no significant differences in the mean CL or CL/F values between any of the dose groups. However, the individual CL and CL/F values for patients at the highest dose level were outside of the 99% confidence interval for their respective ranges, suggesting the possibility of a departure from linear pharmacokinetics at this dose. The individual CL values were in close agreement with respective CL/F values (P = .02, paired t test). This, coupled with the similarity of the t1/2,z observed after IV and PO treatment, provides evidence that the pharmacokinetics of SarCNU are independent of the route of administration.



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  		Fig 3. Scatterplots demonstrating the relationships between the plasma clearance rate (CL) and CL/F, and the 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) dose administered by the intravenous (A) and oral (B) routes. Points are the observed values of individual patients. Lines represent the mean value for the entire patient population.

 
The influence of repetitive dosing and of the relative sequence of IV and PO administration on SarCNU pharmacokinetics was investigated by comparing the total plasma clearance rates of patients having received one or two doses by the same or different routes of administration during the first cycle of treatment. The mean CL of patients given SarCNU by the IV route on day 1 (20.4 ± 9.1 L/h/m2, n = 23) was indistinguishable from that of patients given SarCNU by the IV route on day 5 (21.4 ± 8.4 L/h/m2, n = 11) after receiving a PO dose on day 1. Likewise, there was no significant difference in the mean CL/F of patients given SarCNU by the PO route on day 1 (43.6 ± 38.5 L/h/m2, n = 11) compared with that of patients given SarCNU by the PO route on day 5 (26.8 ± 13.2 L/h/m2, n = 31) after receiving an IV dose on day 1. Although the abbreviated sampling schedule on day 9 did not permit determination of the CL/F, a comparison of the Cmax values of individual patients following their first and second PO treatment revealed a close correspondence (P = .003, paired t test). These data are consistent with the conclusion that SarCNU pharmacokinetics is not influenced by repetitive administration or the route of administration.

Pharmacodynamics
The degree of thrombocytopenia (maximum percentage of change in platelet counts) was more highly correlated with the SarCNU dose (R2 = 0.65, P < .001) than with the AUC (R2 = 0.53, P < .001) or the Cmax (R2 = 0.40, P < .001) after the first PO treatment of cycle 1. Fitting the sigmoidal Emax model to the dose and AUC versus maximum percent change data provided best-fit equations that, in general, showed good agreement with the experimental data (R2 = 0.65 and R2 = 0.55, respectively). The dose or AUC corresponding to the 50% maximum effect level were 643 mg/m2 and 33.5 µg x h/mL, respectively, and the sigmoidicity parameters were 2.6 and 6.7, respectively. The Emax model fit the AUC versus percentage change data particularly well above the AUC50 level, but below that level, there were several patients who demonstrated decreases in platelet counts far greater than that which would be predicted from the model. Of these seven data points above the 95% confidence interval for the fit, all were from patients exhibiting significantly higher CL/F values than the study group (mean CL/F, 69 ± 33; P < .001). In addition, five of these patients demonstrated low oral bioavailability (below the 99% confidence interval) and/or plasma concentration data from additional cycle 1 PO treatments, indicating that the AUC following the first PO dose did not accurately reflect total exposure to SarCNU for these patients during the cycle. If these five data points are eliminated from consideration, the fit of the Emax model to the AUC versus percentage change data is much better (R2 = 0.79). The remaining two patients outside of the 95% confidence interval for the AUC versus percentage change fit also showed a greater decrease in platelet counts that would be predicted by the model at their respective doses. This indicates that, although increasing levels of drug exposure may be a primary determinant of the development and degree of thrombocytopenia, individual diversity associated with covariates such as disease state, genetics, age, sex, or other factors may also play an important role in patient sensitivity to the myelosuppressive effects of SarCNU.

Antitumor Activity
Eight patients had stable disease. There were no partial or complete responses documented.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
SarCNU was developed because in preclinical studies there was evidence that SarCNU was significantly more efficacious than BiCNU in the human glioma xenograft model8 and that, unlike BiCNU, which enters cells via passive diffusion, SarCNU is transported into cells via the extraneuronal monoamine transporter.5,7 Furthermore, in vitro evidence with human glioma cell lines indicates that the presence of the extraneuronal transporter in glioma cell lines increases the antitumor activity of SarCNU.6

The AUC and the Cmax increased proportionally with the dose after both IV and PO administration. At the highest dose, however, CL and CL/F values for the two patients in the group were in the lowest part of the observed range. Although the small sample size and the high variability in the CL and CL/F values limit the usefulness of statistical analysis, the possibility of nonlinear pharmacokinetics at this dose must be considered. This may be the result of saturation of an elimination mechanism or of the extraneuronal transporter that accommodates SarCNU. Evidence that SarCNU pharmacokinetics is independent of the route of administration is provided by the significant correlation of the individual AUC and t1/2,z values observed after IV and PO dosing and by the observation that the sequence of IV or PO administration did not alter CL or CL/F values. The fact that Cmax values were not significantly different after repeated PO administration indicates that the pharmacokinetics are also independent of the number of doses. Oral bioavailability was high (80% ± 37%). Interpatient variability of the pharmacokinetic parameters determined was, in general, moderate, with CV values ranging from 35% to 60%. Variability of the CL/F values was somewhat higher (CV, 75%). It appears that the dose and, to a lesser extent, the AUC of SarCNU pharmacokinetics correlate with the degree of thrombocytopenia.

BiCNU has been reported to have a biologic half-life of 15.6 minutes and a CL of 56 mL/min/kg, as compared to a half-life of 67 minutes and CL of 9 mL/min/kg for SarCNU.17 This indicates that BiCNU is eliminated more rapidly and, therefore, at equimolar doses, SarCNU will exhibit a substantially greater AUC (plasma concentration over time) compared with BiCNU. This, coupled with the fact that SarCNU was more potent in vitro than BiCNU in human glioma specimens at equimolar concentrations,2,3 indicates that SarCNU has a greater potential for a therapeutic impact.

The DLT of SarCNU was myelosuppression similar to other chloroethylnitrosoureas. An analysis of the nadir platelet counts and neutrophil counts in the limited number of patients who received more than one cycle of chemotherapy did not indicate that SarCNU causes cumulative myelosuppression. Nonhematologic toxicities were mild, with the exception of one death from pulmonary toxicity associated with SarCNU. The MTD was 1,075 mg/m2, and the dose used in phase II trials was 860 mg/m2 PO on days 1, 5, and 9 every 6 weeks. No patient has initially received this dose because, in the study, the dose for either day 1 or 5 of the first cycle was given IV to facilitate comparative pharmacokinetics. Phase II trials have already begun at this dose. Because there is no significant relationship between body size and SarCNU plasma clearance rates, the results do not support determining dose on body size (weight or surface area). Thus, an alternative dose schedule could be based on the median or average dose at the 860/m2 level (1,450 or 1,500 mg, respectively). However, in view of the narrow range of body surface area (CV ± 11%), patients outside of this range may exhibit substantially different pharmacokinetic behavior. SarCNU is a well-tolerated oral chloroethylnitrosourea, and the peak plasma concentration achieved in vivo is higher than the predicted plasma concentration obtained using the median lethal dose in mice.3 Thus, assuming the preclinical in vitro and in vivo results are predictive, SarCNU should be superior to BiCNU in patients with gliomas. Phase II trials of SarCNU are being performed in patients with gliomas and advanced colon cancer because these tumors are known to express the extraneuronal monoamine transporter.18


   NOTES
 
Supported by a National Cancer Institute grant, RO1-CA-78205, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, to L.P.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Sumai T, Kato T, Hisamatsu T: 2-Chloroethylnitrosourea congeners of amino acid amides. J Med Chem 25:829–832, 1982[CrossRef][Medline]

2. Panasci LC, Dufour M, Chevalier L, et al: Utilization of the HTSCA and CFU-C assay to identify two new 2-chloroethylnitrosourea congeners of amino acid amides with increased in vitro activity against human glioma as compared to BCNU. Cancer Chemother Pharmacol 14:156–159, 1985[CrossRef][Medline]

3. Skalski V, Rivas J, Panasci LC, et al: The cytotoxicity of sarcosinamide chloroethylnitrosourea (SarCNU) and BCNU in primary gliomas and glioma cell lines: Analysis of data in reference to theoretical peak plasma concentrations in man. Cancer Chemother Pharmacol 22:137–140, 1988[Medline]

4. Begleiter A, Lam H-YP, Goldenberg GJ: Mechanism of uptake of nitrosourea by L5178Y lymphoblasts in vitro. Cancer Res 37:1022–1027, 1977[Abstract/Free Full Text]

5. Noë AJ, Malapetsa A, Panasci LC: Transport of (2-chloroethyl)-3-sarcosinamide-1-nitrosourea in human glioma cell line, SK-MG-1, is mediated by an epinephrine sensitive carrier system. Mol Pharmacol 44:204–209, 1993[Abstract]

6. Noë A, Malapetsa A, Panasci LC: Altered cytotoxicity of (2-chloroethyl)-3-sarcosinamide-1-nitrosourea in human glioma cell lines SK-MG-1 and SKI-1 correlates with differential transport. Cancer Res 54:1491–1496, 1994[Abstract/Free Full Text]

7. Noë A, Marcantonio D, Barton J, et al: Characterization of the catecholamine extraneuronal uptake-2 carrier in human glioma cell lines SK-MG-1 and SKI-1 in relation to SarCNU selective cytotoxicity. Biochem Pharmacol 51:1639–1648, 1996[CrossRef][Medline]

8. Marcantonio D, Panasci LC, Hollingdale MG, et al: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea, a novel chloroethylnitrosourea analogue with enhanced antitumor activity against human glioma xenografts. Cancer Res 57:3895–3898, 1997[Abstract/Free Full Text]

9. Levine BS, Wheeler CW, Tomaszewski JE, et al: Preclinical toxicology studies of SarCNU. Proc Am Assoc Cancer Res 37:A2554, 1996

10. Brown AP, Morrissey RL, Tomaszewski JE, et al: Oral toxicity of (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU) in the rat. Proc Am Assoc Cancer Res 38:A13, 1997

11. Supko JG, Garcia-Carbonero R, Puchalski TA, et al: Plasma pharmacokinetics and bioavailability of 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea after intravenous and oral administration to mice and dogs. Cancer Chemother Pharmacol 48:202–208, 2001[CrossRef][Medline]

12. Supko JG, Phillips LR, Malspeis L: Specific high-performance liquid chromatographic assay with ultraviolet detection for the determination of 1-(2-chlroethyl)-3-sarcosinamide-1-nitrosourea in plasma. J Chromatogr B Biomed Appl 677:351–362, 1996[CrossRef][Medline]

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Submitted March 8, 2002; accepted September 30, 2002.


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