Pharmacokinetic and Biochemical Studies on Acivicin in Phase I Clinical Trials1

[CANCER RESEARCH 45, 4460-4463, September 1985]

J. Patrick McGovren,2 Evelyn A. Pratt, Robert J. Belt,3 Sarah A. Taylor, Robert S. Benjamin, Bach Ardalan,4 and Takao Ohnuma

The Upjohn Company, Kalamazoo, Michigan 49001 [J. P. M., E. A. P.]: University of Kansas Medical Center, Kansas City, Missouri 64128 [R. J. B., S. A. T.]; M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030 [R. S. B.J; City of Hope National Medical Center, Duarte, California 91010 [B. A.]: and Mount Sinai Medical Center, New York, New York 10029 [T. O.]

ABSTRACT were noted in a Phase II study of acivicin on the x5 schedule in 20 previously untreated patients with advanced colorectal car Acivicin pharmacokinetics were studied in Phase I patients cinoma (6). receiving i.v. treatment on single-dose or daily x5 (daily times Phase I studies on acivicin were conducted on x1, x5, 24-h five doses) regimens repeated every 3 weeks. In 14 patients, the infusion, and 72-h infusion schedules. Toxicity was found to be time course of plasma concentrations was characterized by a schedule-dependent, with myelosuppression being dose-limiting biexponential equation with a terminal (elimination-phase) half- on the x5 schedule and CNS disturbances predominating on life of 9.92 Â±3.91 h (mean Â±SD), distribution phase half-life of x1, 24-h infusion, and 72-h infusion schedules (7-11). The 0.32 Â±0.28 h, total body clearance of 1.69 Â±0.48 liters/h/m2, pharmacokinetics of acivicin in patients treated on the two infu and volume of distribution of 21.79 Â±2.94 liters/m2. Acivicin sion schedules were described previously (10, 11). We report kinetics appeared to be dose-independent over the range of 8.5- here the pharmacokinetic data from patients treated on x1 and 150 mg/m2/day. Urinary excretion of intact acivicin in nine pa x5 schedules in four institutions (five patients from the University tients ranged from 2-42% in the first 24 h following administra of Kansas, seven from City of Hope National Medical Center, tion; interpatient variability in urinary excretion was large, but three from the M. D. Anderson Hospital and Tumor Institute, and daily urinary recovery within patients on the daily x5 schedule six from Mount Sinai Medical Center). was quite consistent. Measurements of acivicin effects on the activity of carbamyl MATERIALS AND METHODS phosphate synthetase II (CPS II) were conducted using leuko cytes and/or malignant ascites of three colon cancer patients. Clinical Methods. Pharmacokinetic and biochemical studies were Acivicin given to one patient at 8.5 mg/m2/day on the daily x5 conducted in advanced solid tumor patients receiving acivicin in Phase I schedule caused a 70% reduction in leukocyte CPS II activity clinical trials conducted under the auspices of the Investigational Drug within 5 h after therapy was initiated. Leukocyte CPS II activity Branch, Cancer Therapy Evaluation Program, Division of Cancer Treat remained suppressed at this level over the 5-day dosing regimen. ment, National Cancer Institute. Previous reports have described the In this patient, CPS II activity in malignant ascitic cells had treatment protocols and results pertaining to efficacy and toxicity ob served in studies conducted at the University of Kansas Medical Center decreased by 75% on day 4 of the daily x5 regimen. On the single dose schedule, treatment of two patients with 100 mg/m2 (7), Mount Sinai School of Medicine (8), and the M. D. Anderson Hospital and Tumor Institute (9). caused leukocyte CPS II activity to decrease by >90% within 4 Methods were similar at City of Hope Hospital, where a total of 12 h of treatment with gradual recovery over the next 2 days. adult patients (5 male, 7 female) with advanced solid cancers refractory to conventional treatment received a total of 15 courses. Eight patients were treated on the xl schedule (two at 40, one at 60, three at 100, INTRODUCTION and two at 150 mg/m2), and four patients were treated on the x5 schedule (one at 5.4 mg/mj/day and three at 8.5 mg/m2/day). All patients Acivicin [(aS,5S)-a-aminc-3-chloro-2-isoxazoline-5-acetic acid; had received prior chemotherapy, and four had received prior radiation NSC 163501; AT-125] is a fermentation-derived amino acid therapy. antitumor agent currently being evaluated in Phase II clinical trials Patients received acivicin as an i.v. infusion over periods ranging from (1). Acivicin is a glutamine antagonist and is thought to kill cells 1 min to 1.75 h. For pharmacokinetic studies, serum or plasma was through inhibition of several glutamine-dependent amidotransfer- separated from blood samples collected at intervals post-infusion and ases, including cytidine triphosphate synthetase and CPS II5(2- frozen. Urine was also collected over defined intervals. The urinary volume was recorded, and aliquots were frozen. Plasma and urine 4), key enzymes in purine and pyrimidine biosynthesis. A prelim inary report of objective antitumor activity against human non- specimens were shipped on dry ice to The Upjohn Company for assay. In addition, the effect of acivicin treatment on the activity of CPS II was small cell lung cancer has appeared (5). No objective responses studied in the leukocytes and/or ascitic cells of three colon cancer 1T. Ohnuma acknowledges support of contract N01 -CM-97275 with the Division patients at City of Hope National Medical Center. Serum chemistry values (serum bilirubin, serum glutamic-oxaloacetic of Cancer Treatment, National Cancer Institute. 2To whom requests for reprints should be addressed, at Cancer and Viral transaminase; serum glutamic-pyruvate transaminase) were used to Diseases Research, The Upjohn Company, Kalamazoo, Ml 49001. classify the degree of hepatic dysfunction as: none (enzymes or bilirubin 3 Present address: 6724 Troost, Kansas City, MO 64131. 'Present address: University of Southern California, Comprehensive Cancer < 1.25 times normal limits), mild (enzymes or bilirubin >1.25-2.50 times lab normal), moderate (enzymes or bilirubin >2.50-5.00 times lab nor Research Center, Los Angeles, CA 90033. 5 The abbreviations used are: CPS II, carbamyl phosphate synthetase II; t^, mal), and severe (enzymes or bilirubin >5.00 times lab normal). No distribution-phase half-life; f1M.elimination-phase half-life; AUC. total area under the patients studied had compromised renal function based on serum cre- plasma concentration-time curve; CU. total body clearance; VÂ«., volume of distribution; CNS, central nervous system; x1, single dose every 3 weeks; x5, atinine and blood urea nitrogen values. daily times five doses repeated every 3 weeks. Analytical Methods. Plasma and urine specimens were assayed for Received 12/7/84; revised 4/9/85; accepted 5/31/85. acivicin by a microbiological method using Bacillus subtilis UC-902. This

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1985 American Association for Cancer Research. ACIVICIN PHARMACOKINETICS AND BIOCHEMICAL EFFECTS method was described previously in detail (12). Patients were not con results reported previously from the University of Kansas (7), Mt. currently treated with antibiotics which could interfere with the micro Sinai Medical Center (8), and M. D. Anderson Hospital and Tumor biological assay. Whenever possible, sufficient pretreatment serum or Institute (9). Mild to moderate CMS toxicity was observed on plasma and urine were obtained for preparation of standard curves using each patient's own fluids. Otherwise, plasma or urine from normal human both x1 (8 of 8 patients) and x5 schedules (1 of 3 patients) and consisted of lethargy, weakness, disorientation, somnolence, subjects was used in preparation of standards. Each sample was as sayed at two dilutions, and the results were averaged. Analytical sensi confusion, vivid dreams, and hallucinations. The onset of these tivity was approximately 0.05 /Â¿g/mlin plasma and 0.6 Â¿ig/mlin urine. effects was usually the second day after initiation of therapy. Also, as described previously (12), bioautographic studies were con Toxicity persisted for 2-3 days after therapy ended. Myelo- ducted on selected plasma and urine samples to determine the specificity suppression consisting of mild thrombocytopenia was observed of the microbiological assay for unchanged acivicin. In agreement with in only one patient treated on the x1 schedule (100 mg/m2), in previous studies (10, 11), only one zone of inhibition per sample was agreement with previous results (7). Myelosuppression was not observed in the bioautographic studies, and, in each case, the R( of the observed in x5 patients receiving 5.8 or 8.5 mg/m2/day. This zone corresponded to that of intact acivicin. was consistent with results from the x5 study conducted at Mt. As an additional check on assay specificity, selected urine specimens from acivicin-treated patients were assayed both by the microbiological Sinai Medical Center, which showed myelosuppression (leuko- method and by a murine L1210 cell tube-dilution growth inhibition assay penia and neutropenia) to be significant at >12 mg/m2/day and (13). This was done to determine if urine contained substances in addition to be the dose-limiting toxicity at 20 mg/m2/day (8). No partial or to acivicin which would inhibit the growth of mammalian cells while complete responses were noted in the City of Hope Hospital allowing the growth of the bacterial assay organism. On four urine study. One patient with adenocarcinoma of the large bowel had samples containing between 12 and 39 ^g/ml acivicin bioequivalents stable disease and a reduction in carcinoembryonic antigen levels based on the B. subtilis assay, values determined by the L1210 assay from 150 to 60 ng/ml upon treatment with 8.5 mg/m2/day x5. differed by -8 to +14%, suggesting that the microbiological assay Acivicin Pharmacokinetics in Plasma. In patients receiving accurately reflected the concentration of substances toxic to mammalian doses less than 8.5 mg/m2/day, plasma concentrations could be cells. This finding combined with the bioautographic results suggested that only intact acivicin was measured, and all pharmacokinetic calcula quantitated through only 6 h or less, and these data are not tions were done under that assumption. included. Table 1 shows individual and mean pharmacokinetic Pharmacokinetic Analysis. Acivicin plasma concentration-time data parameters in 15 patients treated with doses ranging from 8.5- from all patients but one were described adequately by a biexponential 150 mg/m2. Chart 1 shows the time course of acivicin concen equation. In one patient (No. 4), a monoexponential equation yielded a trations in plasma in three patients (Nos. 02, 04, and 17). A better fit to the data. Computer fitting was done with the nonlinear biexponential equation adequately described the time course of parameter estimation program, NONLIN (14), on an IBM digital computer post-infusion plasma concentrations in 14 of 15 patients; a using routines for the one- or two-compartment open models for drug distribution phase was not detectable in patient 4's plasma disposition with zero-order input. The duration of zero-order input was varied according to individual patient infusion lengths. The data points concentrations, which declined monoexponentially (earliest sam were weighted using the factor 1/y2 in the fitting procedure. Goodness pling time was 5 min post-infusion; Chart 1). The initial distribution of fit was determined from correlation coefficients (r2), residual sums of phase of plasma pharmacokinetics is less evident in patients squares, standard deviations of estimated parameters, and from visual receiving infusions as opposed to bolus injections (15); however, inspection of plots of the predicted and observed concentrations versus the infusion duration was only 15 min in patient 4, and this is not time. Pharmacokinetic parameters were calculated by standard methods believed to be the explanation for the lack of a detectable a- (15). ADC was computed from the parameters of the equations of best- phase in this patient. Values of tv,a varied considerably between fit (15). CU was calculated as dose/AUC, and Vareawas calculated as CLa/ÃŸ,where ÃŸis the first-order rate constant describing the terminal patients but were brief compared to t^a in all patients. Values of fvw ranged from 4.28-17.97 h with a mean Â±SD of 9.92 Â±3.91 elimination phase of plasma level decline. Biochemical Methods. CPS II activity was measured at intervals in h. CU (calculated as dose/AUC) was constant among patients the leukocytes of two patients receiving acivicin on the x1 schedule. In (mean Â±SD = 1.69 Â±0.48 1/h/m2), reflecting the direct propor one patient treated on the x5 schedule, CPS II activity was measured in tionality between dose and AUC (r2 = 0.8507). Vareashowed little the leukocytes at intervals over 5 h during the first day of treatment and interpatient variability (21.79 Â±2.94 liters/m2). The magnitude of then prior to drug administration on days 2, 3, 4, and 5. In the latter Vareaapproximated total body water, suggesting that acivicin was patient, malignant ascites was also collected for measurement of CPS II distributed throughout the body but was not highly bound in activity prior to treatment on day 1 (baseline) and day 4. Approximately tissues. Acivicin pharmacokinetics appeared to be dose-inde 10 ml of blood or ascitic fluid were withdrawn at each time for CPS II pendent over the range of 8.5-150 mg/m2. measurements. A buffy coat was isolated from heparinized whole blood or ascitic fluid following low-speed centrifugation (150 x g, 5 min). Patient 6, who had the longest tv,avalue reported to date, had Contaminating erythrocytes were removed by brief hypotonie shock and acivicin plasma levels of 0.15, 0.16, and 0.17 /ig/ml just prior to recentrifugation (16). The leukocyte or ascitic cell pellets were immedi dosing on days 3, 4, and 5 of the 5-day regimen. Patients 13 ately homogenized by hand in 1 volume of a buffer consisting of 30% and 14 had no measurable drug accumulation between days 1 dimethyl sulfoxide, 5% glycerin, 0.1 M Tris-HCI (pH 8.4), 0.1 M KCI, 0.2 and 5. mW EDTA, and 0.2 mw dithiothreitol. After centrifugation for 3 min at At the recommended Phase II dose of 15 mg/m2/day on the 12,000 x g, supernatant fractions were immediately assayed for CPS II activity by determination of 14C incorporation from NaH14CO3 into N- daily x5 schedule (8), peak plasma levels of approximately 1 fig/ [14C]carbamyl-L-aspartate (17). ml were achieved (Chart 1). The maximum tolerated dose of 150 mg/m2 given on the x1 schedule yielded peak levels of approx

RESULTS imately 10 ng/m\ (Chart 1). The latter schedule was not recom mended for Phase II studies because of CNS toxicity (7). Clinical Observations. Toxic effects of acivicin observed in Urinary Excretion. Table 2 shows the daily percent of dose patients treated at City of Hope Hospital were consistent with excreted in the urine as intact acivicin by patients on x1 and x5

CANCER RESEARCH VOL. 45 SEPTEMBER 1985 4461

Table 1 Pharmacokineticparameters in acivicin-treated patients

of hepatic day Dose length Patient66161313141417151813745892Mean'DegreedysfunctionNoneNoneMildModerateModerateNoneNoneNoneNoneMildNoneMildSevereMildNoneMildNoneNoneTreatmentSchedule(mg/m2/day)x5 studied (h)0.0330.0330.2500.4170.4171.0831.0830.2501.7500.2500.2500.2500.0170.2500.2500.0170.0170.250ttk,(h)0.120.380.140.140.380.161.160.810.210.0980.860.270.780.440.200.070.240.32(liters/m2)22.5420.2615.5022.2118.5520.7835.3618.4623.9021.2625.8024.6221.7227.4121.7420.7519.1621.0321 8.5x5 2 8.5x5 3 9x5 1 12x5 1 12x5 5 12x5 1 12x5 5 15x5 1 18x5 1 20X1X1X1X1X1X1X1X14040608080100100150Infusion1

Â±0.286ttf(h)17.9717.754.289.6810.896.8912.376.2113.808.1010.5214.9613.5612.837.538.997.505.959.92 Â±3.91CU(liters/h/m2)0.870.792.511.591.182.091.982.061.201.821.701.141.111.482.001.601.772.451.69Â±0.48VÂ«. .79 Â±2.94 " First treatment only for patients 6,13, and 14. ^ Mean Â±SD.

Table 2 Table 2 also shows that daily recoveries were quite consistent Urinary excretion of acivicin within patients studied on successive days on the x5 schedule. of daily dose in Effect of Hepatic Disease on Acivicin Pharmacokinetics. day:111â€”â€”â€”9415656422212â€”19â€”â€”â€”â€”â€”â€”36â€”3â€”24-h urine on When pharmacokinetic indices of drug elimination (fw, CU, Patient1920211613141513452Schedulex5XSxSx5xSX5x5X1X1X1X1X1Dose(mg/m2/day)1.51.56.8912121840408080150% extent of urinary drug excretion) were related to the degree of â€¢361540â€”â€”â€”â€”â€”â€”â€”â€”41632â€”23â€”â€”â€”â€”â€”â€”â€”â€”516â€”â€”36â€”â€”â€”_â€”__â€”â€”hepatic dysfunction (Table 1), no consistent relationships were noted. However most patients studied had no or mild hepatic impairment, and no firm conclusions can be drawn about liver function effects on acivicin disposition. Biochemical Effects of Acivicin Treatment. Biochemical studies were carried out in three colon cancer patients who had leukocyte and/or malignant ascites collections before and after treatment. Chart 2 shows the time course of CPS II activity of the leukocytes and malignant ascites in a patient who received " Not determined. 8.5 mg/m2/days x5. Both leukocytes and ascitic cells demon strated a similar baseline activity of 800 pmol/h/mg protein. During the first 5 h of the study there was a 70-75% reduction in the specific activity of CPS II, which remained suppressed for

Chart 1. Time course of acivicin plasma concentrations in patients 2 (O, 150 mg/m2 x1). 4P, 80 mg/m2 x1), and 17 (A, 15 mg/m2/day x5). The lines were drawn using the computer-fitted pharmacokinetic parameters. 3 (hr) (days) schedules. Considerable variability between patients was noted, TIME with percentages ranging from 2-42% of the daily dose. These Chart 2. Time course of CPS II specific activity in two patients receiving 100 values are generally consistent with urinary recoveries reported mg/m2 xl p and A, leukocytes) and in one patient receiving 8.5 mg/m2/day x5 previously in 24-h infusion and 72-h infusion studies (10, 11). (â€¢,leukocytes;O, malignantascites).

CANCER RESEARCH VOL. 45 SEPTEMBER 1985 4462

5 days in both normal and neoplastia cells. CPS II activity was to drug- or metabolite-induced biochemical changes. In the latter not followed long enough for observation of recovery. The initial regard it is interesting that the onset and duration of behavioral carcinoembryonic antigen of this patient was 150 ng/ml which disturbances is comparable to the time course of CPS II inhibi with treatment decreased to 60. Chart 2 also shows the time tion. course of leukocyte CPS II activity in two patients who received acivicin at 100 mg/m2 x1. There was >90% reduction in the ACKNOWLEDGMENTS specific activity of CPS II 4 h after administration of drug with The assistance of Nurit Friedman in data management at Mt. Sinai Medical gradual restitution of activity to baseline over the next 2 days. Center is gratefully acknowledged. We also thank Laura Timmins at The Upjohn Comparison of leukocyte CPS II inhibition demonstrates a more Company for assistance with pharmacokinetic analysis and tabulation of data. prolonged inhibition with the x5 schedule but a more pronounced inhibition at the much higher dose given on the x1 schedule. REFERENCES

1. Poster, D. S., Bruno, S., Penta, J., Neil, G. L., and McGovren, J. P. Acivicin: an antitumor antibiotic. Cancer Clin. Trials, 4: 327-330. 1981. DISCUSSION 2. Neil, G. L, Berger, A. E., McPartland, R. P., Grindey, G. B., and Bloch, A. Biochemical and pharmacological effects of the fermentation-derived antitumor These studies demonstrated that acivicin pharmacokinetics in agent, (Â«S,5S)-a-amino-3-chloro-4,5-dihydro-5-isoxazole acetic acid (AT-125). Cancer Res., 39: 852-856,1979. patients treated on x1 or x5 schedules are consistent with 3. Neil, G. L., Berger, A. E., Bhuyan, B. K., Blowers, C. L., and Kuentzel, S. L. previous findings on 24- and 72 h-infusion schedules (10, 11). Studies of the biochemical pharmacology of the fermentation-derived antitumor Total body clearance on the 72-h infusion schedule was approx agent, (Â«S,5S)-a-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125). imately 1.9 liters/h/m2 (11), as compared to approximately 1.7 Adv. Enzyme Regul., 17: 375-398,1979. 4. DentÃ³n, J. E., Lui, M. S., Aoki, T., Sebolt, J., and Weber, G. Rapid in vivo liters/h/m2 in these studies. Values of fw (means of 7-10 h) and inactivation by acivicin of CTP synthetase, carbamoyl phosphate synthetase *%â€ž(0.3-0.5h) were also similar on the four schedules tested to II, and amidophosphoribosyltransferase in hepatoma. Life Sci., 30; 1073-1080, 1982. date. 5. Maroun, J., Makysmiuk, A., Eisenhauer, E., Stewart, D., Young, V., and Pater, Acivicin appears to be cleared primarily by non-renal mecha J. A Phase II trial of acivicin (AT-125, NSC 163501) in metastatic non-small cell lung cancer (NSCLC). Proc. Am. Soc. Clin. Oncol., 3. 218,1984. nisms as shown by the percent recovery of intact drug in the 6. Maroun, J., Fields, A. L., Pater, J. L., Stewart, D. J., Cripps, C., and Eisenhauer, urine (Table 2). This finding suggests that hepatic metabolism E. 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CANCER RESEARCH VOL. 45 SEPTEMBER 1985

J. Patrick McGovren, Evelyn A. Pratt, Robert J. Belt, et al.

Cancer Res 1985;45:4460-4463.

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