Phase I/Pharmacokinetic RÃ©Ã©Valuationofthiotepa1

(CANCER RESEARCH 51, 3171-3176, June 15, 1991] Phase I/Pharmacokinetic RÃ©Ã©valuationofThioTEPA1

Peter J. O'Dwyer,2 Frank LaCreta, Paul F. Engstrom, Ruth Peter, Laura Tartaglia, Diane Cole, Samuel Litwin, Joseph DeVito, David Poplack, Robert J. DeLap, and Robert L. Comis Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 fP. J. O'D., F. L., P. F. Â£.,R. P., S. L., R. L C.J; Pediatrie Branch, ,\ational Cancer Institute, Bethesda. Maryland 20892 Â¡L.T., D. Câ€žD.P./; and Lederle Laboratories. Pearl River, ,Vw York 10965 Â¡J.lÃ¬.,R.J. D.]

ABSTRACT dermatologica! effects and mucositis have been observed (2, 3). Because the initial evaluation of Ar,A",Ar"-triethylenethiophosphor- Preclinical data indicate that, as with other alkylating agents, antitumor activity bears a close relationship to dose (8). The amide (thioTEPA) preceded the standardized approach to the Phase I promising results of initial high-dose studies suggest that a trials, uncertainty surrounds the recommended dose. Since it has recently been demonstrated that an almost 100-fold increase in dose can be dose-response relationship may also exist for human tumors administered in bone marrow transplant regimens, we conducted a Phase (9). Since the early studies of thioTEPA used multiple small I rÃ©Ã©valuationofthioTEPA. ThioTEPA was administered i.v. in 50 ml daily doses, from which subsequent intermittent i.v. dose regi 5% dextrose in water over 10 min. Twenty-seven patients were entered mens were derived, we wished to establish a maximum tolerated at doses ranging from 30 to 75 mg/m!. The major toxic effect was dose of thioTEPA by intermittent i.v. administration in a phase myelosuppression; thrombocytopenia â€¢â€¢â€¢grade3 occurred in four of seven 1 study. patients, and leukopenia - grade 3 in two of seven patients at 75 mg/m2. The development of a gas Chromatographie assay for thio Among eight patients at 65 mg/m2 only two had '> grade 3 myelosuppres TEPA has facilitated the study of its pharmacology in humans sion making this the recommended new phase II dose for the majority of (10, 11). Egorin et al. (12) have investigated the pharmacoki- patients. Moderate (grade 2) easily controlled nausea and vomiting was netic behavior of thioTEPA in high-dose regimens. They the only other major side effect. There was no alopecia or mucosal or neurological toxicity. Three partial remissions were observed among nine showed rapid plasma clearance of the parent compound and previously treated ovarian cancer patients. Plasma concentrations of negligible conversion to TEPA, the major metabolite of thioTEPA and its major active metabolite triethylenephosphoramide thioTEPA. Thus in high-dose regimens, the parent compound (TEPA) were measured by gas Chromatograph). The half-life of thio accounts for the bulk of the alkylating activity. These investi TEPA ranged from 51.6 to 211.8 min, and its pharmacokinetics was dose gators also described the slow plasma clearance of TEPA, levels dependent; total body thioTEPA clearance decreased with increasing of which changed little during the 6-h sampling period (13). dose. The half-life of TEPA was considerably longer than that of the Strong et al. (14) noted similar findings in rhesus monkeys. parent compound (3.0 to 21.1 h); as a result, the area under the plasma The kinetics of thioTEPA and TEPA has not been fully de concentration-time curve (AUC) of TEPA was severalfold greater than scribed at standard doses in adult humans. We hypothesized that of the parent compound. The ratio of TEPA AUC to thioTEPA that at lower doses, active metabolites may play a more impor AUC decreased with increasing dose, suggesting that formation of TEPA tant role in the action of thioTEPA. To reevaluate standard is a saturable step in elimination. The AUC and total body clearance of thioTEPA, but not of TEPA, were closely correlated with neutrophil but doses of thioTEPA and to further characterize its pharmacology at these doses, we conducted a phase I/pharmacokinetic study- not platelet toxicity. in patients with advanced cancer. INTRODUCTION MATERIALS AND METHODS ThioTEPA,1 an alkylating agent developed in the 1950s (1), has recently been the subject of renewed interest as a result of Patient Population. Patients eligible for this study had a histolÃ³gica! diagnosis of cancer and had exhausted the standard therapeutic options its incorporation into regimens using autologous bone marrow transplant rescue at doses of up to 1000 mg/m2 (2, 3). Early for their disease. They were less than 70 years old with an Eastern Cooperative Oncology Group performance status of 0-2. They had studies suggested a role for thioTEPA in breast and ovarian adequate bone marrow (WBC > 3000/mm1; platelets > 100.000/mm'). cancers (4, 5), but the drug was largely abandoned in favor of liver (bilirubin < 1.5 mg/dl). and kidney (creatinine < 1.5 mg/dl) other alkylating agents in the 1970s. Formal Phase I testing function. There was no limit on prior therapy, and all patients gave was not performed, and recommended doses varied widely. written informed consent in accordance with Federal, state, and insti More recently, a combination regimen incorporating thioTEPA tutional guidelines. Patients were excluded if they had a significant has been tested in breast cancer (thioTEPA dose, 12 mg/ pleural or peritoneal fluid collection, heart disease (recent myocardial m2); this combination [vinblastine-doxorubicin (Adriamycin)- infarction, uncontrolled congestive failure, or frequent angina), or ra thioTEPA-halotestin] has shown activity in relapsed breast diotherapy to >50% of the pelvis and lumbar spine. Prior to therapy a medical history, physical examination, complete cancer and is being evaluated in the initial therapy of this blood count, biochemical profile, urinalysis, electrocardiogram, and disease (6, 7). The toxicity of thioTEPA, both at standard doses chest X-ray were performed. Patients were monitored with weekly blood and at doses less than 1000 mg/m2, appears to be confined to counts and biochemical profiles and clinical examinations on each the bone marrow (2, 3). At higher doses, neurological and course. Doses were reduced if necessary based on toxicity. Doses were not escalated within patients. Results are reported using the consensus Received 4/11/90; accepted 4/9/91. toxicity criteria.4 Patients with measurable disease were evaluated (usu The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in ally by scan or X-ray) for every other course: those with stable disease accordance with 18 U.S.C. Section 1734 solely to indicate this fact. or better were continued on therapy. Response criteria were standard 1Supported in part by a grant from Lederle Laboratories and by National (15). Cancer Institute Grant CA06927. 2To whom requests for reprints should be addressed, at Fox Chase Cancer Treatment Plan. ThioTEPA was supplied as 15 mg lyophilized pow Center. 7701 Burholme Avenue. Philadelphia. PA 19111. der in glass vials by Lederle Laboratories (Pearl River, NY). Reconsti- 3The abbreviations used are: thioTEPA. ,V,A",.V"-triethylenethiophosphoramide (NSC 6396): TEPA. triethylenephosphoramide: AUC. area under the 4Cancer Therapy Evaluation Program. National Cancer Institute. Bethesda. plasma concentration-time curve. MD. 1988. 3171

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1991 American Association for Cancer Research. PHASE I/PHARMACOKINETIC REEVALUATION OF ThioTEPA tution with 3 ml sterile water yielded a solution containing 5 mg/ml. Pharmacodynamic analysis was performed using the NONLIN84 The appropriate dose of thioTEPA was then diluted in 50 ml of 5% computer program (21). Akaike's information criterion was used to dextrose U.S.P. and administered i.v. as a zero-order infusion over 10 determine which model produced the superior fit. min. Drug administration and pharmacokinetic sampling were per formed in the Mary S. Schinagl Clinical Pharmacology Unit at Fox Chase Cancer Center. RESULTS The starting dose. 30 mg/nr, was selected based on the expectation Twenty-seven patients were treated with 66 courses of that extramedullary toxicity would be minimal; doses were escalated in 30% increments. A minimum of three patients were treated at each thioTEPA. Their demographic characteristics are summarized dose level. Accrual to a level was expanded if severe or unexpected in Table 1. One-third of the patients had ovarian cancer, reflect toxicity was encountered. The recommended phase II dose was defined ing a referral based on the known activity of the drug in this as the dose at which fewer than 50% of patients had grade III or IV disease. myelosuppression or grade II-IV extramedullary toxicity. Courses were Five dose levels were studied ranging from 30 to 75 mg/m2, repeated every 3-4 weeks. with a minimum of three patients at each level. Accrual to the Pharmacokinetic Sampling. Blood samples (5 ml) were drawn into first level (30 mg/m2) was expanded to six patients when a 37- hcparinizcd tubes and centrifuged immediately at 4Â°C.Plasma was year-old male with disseminated adenocarcinoma of unknown separated and, for over 80'< of the samples, was extracted immediately: primary developed grade 4 thrombocytopenia and died at home during the course of the study it was demonstrated that complete recovery of drug and metabolite could be obtained from plasma stored of a probable intracranial hemorrhage. Subsequent review of at â€”70Â°C.Theextraction procedure was as previously described (II). this patient's histopathology revealed replacement of bone mar For analysis of thioTEPA levels 200 ^1of plasma were shaken with 0.8 row by tumor infiltration. When excessive toxicity was identi ml of ethyl acetate with 1 ng/m\ diphenhydramine (internal standard) fied at 75 mg/m2, an intermediate dose of 65 mg/m2 was in I.5-ml polypropylene tubes and centrifuged briefly to separate the determined to be suitable for further phase II evaluation. layers. The organic layer was aspirated, evaporated to dryness under a Myelosuppression. The major and dose-limiting toxicity was stream of nitrogen at room temperature, and stored immediately at -70Â°C. For TEPA levels, a similar procedure was used, except that myelosuppression affecting both leukocytes and platelets, as summarized in Tables 2 and 3. Leukopenia was clearly dose chloroform (containing I Mg/ml diphenhydramine) was the extracting solvent. The remainder of the plasma was stored at -70Â°C. Samples related, and grade 3 toxicity occurred in 2 of 8 and 2 of 7 were batched and transported on dry ice for analysis. Pharmacokinetic samples were obtained at baseline (before infusion) Table I Patient characteristics and at 5. 10. 15, 30. 45, and 60 min and 1.5. 2, 3, 6. 12. 18, 24, 36, Entered/evaluableMale/femaleMedian and 48 h after the end of the infusion. Aliquots (5 ml) from each specimen were frozen at -70Â°Cfor later analysis.

Analytical Procedure. Samples were thawed and extracted in ethyl range)Performanceage (yr. (25-74)51392312195310 acetate (for both thioTEPA and TEPA measurements). Drug levels were quantitated using a Hewlett-Packard HP5890 gas Chromatograph status012Prior equipped with a nitrogen-phosphorus detector (Hewlett-Packard, Palo Alto, CA). One-^1 aliquots were injected using a split-splitless injector (split ratio, 20:1). at 260Â°C,onto a Supelco 0.25-mm inner diameter x 30-m SPB-5 capillary column at 230Â°C.The detector temperature was therapyChemotherapyRadiationBothNeitherTumor 300Â°C.The carrier gas was helium flowing at 1 ml/min. Drug levels were derived from standard curves which were prepared daily for thioTEPA (standard obtained from Lederle Laboratories) and TEPA (standard obtained from Dr. G. Sosnofsky, University of Wisconsin, Madison. WI). The assay was linear from 10 ng/ml to 5 /ig/ml, with a typeOvarianColonLungOther27/279/1861 lower level of sensitivity of I ng/ml. Data Analysis. Pharmacokinetic analysis of each patient's plasma samples was carried out using M LAB. a nonlinear curve-fitting program (16). The best fit was determined by application of Akaike's information criterion (17). The half-life for each phase of elimination was obtained by dividing 0.693 by the rate constant for that phase. The AUC was Table 2 Incidence and severity of leukopenia following the first cycle of treatment with thioTEPA derived using the logarithmic trapezoidal method and extrapolated to (grade)No.6 infinity using the terminal rate constant (18). Clearance was calculated Dose(mg/m2)30 by dividing drug dose by AUC. The lack of urine data precluded an estimate of TEPA clearance. The apparent volume of distribution at steady state was calculated using the area under the moment curve (19). 40 3 3 0 012 0 0 Pharmacokinetic/pharmacodynamic relationships were investigated 55 3 1 13220 02 0 using three models: (a) a linear relationship: (/>}an exponential equation 6575WBC 8705 1 00 111 230 240 of the form % change = 100(1 - e-*'AUC) Table 3 Incidence and severity of thrombocytopenia following the first cycle of treatment with thioTEPA where A;is the fitted parameter: and (c) the Hill equation similar to that (grade)No.6 used by Egorin et al. (20): Dose (mg/m2)30 Maximum effect (AUC)* % change = (AUCÂ«,)*+ (AUC)* 40 3 2 0 1 0 0 55 3 2 0 1 0 0 where AUCso is the AUC which produces a half-maximal effect, h is 6575Platelets 8704 3310 3 1030 0241 12 the Hill constant, and the maximum effect is 100. 021 3172

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1991 American Association for Cancer Research. PHASE I/PHARMACOKINETIC REEVALUATION OF ThioTEPA patients at 65 and 75 mg/irr, respectively. No episodes of nausea lasting for weeks after a dose and accompanied by neutropenic sepsis occurred in these patients. Thrombocyto- lethargy and malaise was unresponsive to phenothiazines and ultimately led to the patients' withdrawal from therapy. On the penia was also dose related but was more sporadic; i.e., 4 of 7 patients at 75 mg/irr experienced grade 3 or 4 toxicity, while other hand, the majority of patients required no antiemetics at 65 mg/m2 only 1 of 8 patients was similarly affected. When and sustained no treatment-related interference in their life myelosuppression was analyzed as the percentage of decrease style. It was notable that no patients on this study experienced in count (i.e., pretreatment value - nadir/pretreatment value), alopecia, and the mucosal and neurological effects observed leukopenia and, more markedly, neutropenia were strongly with dose >1 g/nr did not occur. correlated with thioTEPA dose (P = 0.03 and 0.003, respec Response. Evidence of antitumor effect was noted across the tively). The percentage of decrease in platelet count was not, range of doses used. Three of the nine patients with ovarian however, a function of dose (P = 0.34). cancer had partial remissions following treatment; one received Since the median number of courses administered is 2 (range, 30 mg/m2 and two 75 mg/m2. Each had progressed following 1-8), a detailed analysis of cumulative hematological toxicity a minimum of two prior regimens. Maximal tumor shrinkage is fragmentary. Of 3 patients who received 3 courses, 2 required was achieved after two cycles of therapy, and responses lasted dose reduction and/or delay in treatment. An additional 5 2, 5.5, and 6 months. A short-lived (1 month) mixed response patients received 4 to 8 courses; all required dose reduction occurred in a patient with endometrial cancer treated at 75 mg/ and/or treatment delay. Table 4 illustrates how the duration, m2. Three patients (55-65 mg/m2) with tumors of the colon, as opposed to the degree, of myelosuppression influenced sub bladder, and ovary, respectively, had stable disease lasting 4-6 sequent treatment. Slow recovery of blood counts was an im months. portant manifestation of myelosuppression and was more sim Pharmacokinetics. Plasma concentration-time curves of ilar to that seen with nitrosoureas than with cyclophosphamide. thioTEPA and of its major metabolite TEPA were analyzed Other Toxicity. The only other important side effect of using MLAB. The mean pharmacokinetic parameters for thioTEPA administration was nausea and vomiting. The sever thioTEPA and TEPA are detailed in Table 6. The terminal ity of this was variable but appeared to be dose related (Table half-life of thioTEPA ranged from 51.6 to 211.8 min and was 5). In most patients it was easily controlled and was prevented independent of dose. The AUC of thioTEPA was proportional in subsequent courses by the use of standard antiemetics. In to dose (P = 0.001), but not linearly; a striking increase in the two patients, however, a more severe syndrome of protracted AUC occurred at doses >55 mg/m2 (Fig. la). This was accom panied by a decrease in CIT at these doses (Fig. \b). Values Table 4 Evidence for delayed recovery of blood counts as a manifestation of obtained at the two higher doses were significantly different cumulative toxicity in patients treated with thioTEPA from those at the lower doses (Table 4). The VdKdid not vary withtreatment with dose. Dose(mg/m2)3040556575Patientstreated63387No.delay(courses withdosereduction00142 A partial explanation for the dose-dependent behavior of toonset)K5)KD2 thioTEPA was apparent from the TEPA levels. TEPA half- lives were considerably longer than those of the parent com (2.5)4(1, pound and ranged from 3.0 to 21.1 h. The AUC of TEPA was 1.2,4)4(1. severalfold greater than that of thioTEPA, as illustrated for the 1.2,5)No. 65-mg/m2 level in Fig. 2. However, the AUC of TEPA did not increase with dose, suggesting that metabolism to TEPA may Table 5 Nausea and vomiting as a consequence of thioTEPA administration be an enzymatic process which is saturated at the lowest doses affected used in this study. The marked decrease in the ratio of plasma Dose30405565Total patients6338No. (grade)01 TEPA AUC to that of thioTEPA with increasing thioTEPA (2)1 dose supports this conclusion (Fig. lc). The lack of reliable (2)Ia urinary excretion data precluded the description of TEPA (if2 clearance. (1)4 (2) The relationship between renal function and thioTEPA dis 75 3 (2) position was explored by plotting creatinine clearance (derived " This patient had intermittent vomiting before beginning treatment. from a nomogram) against total body clearance of thioTEPA;

Table 6 Pharmacokinetics of thioTEPA and TEPAÂ°

ThioTEPA TEPA

Dose (/jMXmin (Â¿iMXmin TEPA (mg/m2)3040556575n53355rÂ»(min)6.29.311.97.96.0rÂ«(min)78.188.2104.7133.5125.6CMml/min/m2)581.6(67.7)728.0(71)779.0(222)382.6*(59)315.0'(47)(L/m2)65.9(9.70)72.0(11.5)47.3(19.8)68.6(8.78)64.4(6.6)AUCxIO2)3.0(0.4)2.9(0.3)4.5(1.52)9.88(1.59)14.2(2.73)n42355rÂ»(min)478291357442750AUCxIO2)42.7(4.95)48.8(2.45)49.8(17.1)55.0(15.5)35.7(6.6)AUC(AUC thioTEPA)15.2(1.2)13.5(D11.1(1.56)6.5(2.1)2.8(0.7)

" Mean values in parentheses are Standard errors. * Significantly different from 40 mg/m2 (P < 0.05). c Significantly different from 30. 40. and 50 mg/m2 (P < 0.05). 3173

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1991 American Association for Cancer Research. PHASE 1/PHARMACOKINETlC REEVALUATION OF ThioTEPA 20 n a DISCUSSION When thioTEPA was introduced to the clinic, it was evalu I ated by repetitive daily dosing to toxicity (22). Activity was identified in several tumors, but the drug fell into disuse because ID occasional patients developed unexpectedly severe myelosuppression at standard doses. Renewed interest in thioTEPA CL 01 resulted from both the development of methodology for its pharmacological characterization and the demonstration that doses up to 1 g/m2 could be administered if autotransplantation of bone marrow were used. ThioTEPA has generally been used at doses on the order of 12-24 mg/m2 (6, 7, 23) repeated every 4 weeks; however, a formal phase I study of intermittent ad ministration has never been performed. In this phase I study of good-risk patients we have identified a 5-fold higher maximum tolerated dose for thioTEPA at 65 mg/m2. Since, like other alkylating agents, thioTEPA demonstrates a steep dose-re sponse curve in vitro (8, 24) and in vivo (9), these data suggest

MEAN PLASMA DRUG LEVELS 65 MG/SQ.M. I.V.BOLUSTHIOTEPA

o D OC .01 500 1000 1500 2000 TIME [MINUTES] 30 40 50 60 70 80 Fig. 2. Mean plasma levels of thioTEPA and TEPA following treatment of Thio-TEPA Dose (mg/m2) three patients with thioTEPA (65 mg/m2). Fig. I. Relationship of thioTEPA dose to area under the plasma concentration- time curve (a), total body clearance of thioTEPA (b), and ratio of the areas under the concentration-time curves of TEPA to thioTEPA (c). Points, mean; bars, SEM.

no significant relationship was identified. WBC, neutrophil, and platelet toxicity bore no relationship with creatinine clearance. The pharmacokinetic parameters (CIT and AUC) of thio TEPA were closely related to the percentage change in neutrophils (P = 0.0163 and 0.0003, respectively) and total WBC (P = 0.0350 and 0.0020, respectively). In fact, the AUC of thio TEPA was the best predictor of neutrophil toxicity (Fig. 3), and both the AUC and total clearance were superior to dose in determining neutrophil toxicity. r - 0.702 The relationship between the percentage of change in neutro -100-0- ,-0.1063 AUC phil count and thioTEPA AUC was investigated further using 20- the models described in "Materials and Methods." Using these criteria, the best fit was obtained with the exponential model (Fig. 3). The pharmacokinetics of thioTEPA bore no relationship to 10 15 20 25 30 observed decreases in platelet counts. Interestingly, despite the Thio-TEPA AUC (nM*min x 102) fact that it was much greater than the AUC of thioTEPA in Fig. 3. Area under the plasma concentration-time curve of thioTEPA plotted most patients, the AUC of TEPA did not correlate with the against the change in neutrophil count: degree of marrow suppression. Toxicity was similarly unrelated Baseline â€”nadir x 100 to the sum of the AUCs of thioTEPA and TEPA. Baseline 3174

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1991 American Association for Cancer Research. PHASE I/PHARMACOKINETIC REEVALUATION OF ThioTEPA that a limited phase II rÃ©Ã©valuationofthioTEPA may be phamide may variably influence hepatic enzyme systems also indicated. involved in thioTEPA metabolism, interpretation may be com As expected, myelosuppression was dose limiting. At 75 mg/ plicated accordingly. Finally, we have demonstrated in a rat m2 over one-half the patients had grade 3 or 4 thrombocyto- liver perfusion model that hepatic clearance of thioTEPA is penia and/or leukopenia. At these doses, too, delayed recovery nonlinear with respect to the concentration in the perfusate of marrow function became increasingly evident, and several (28), an observation consistent with the results of this study in patients experienced cumulative myelosuppression. This sug humans. It remains possible, nonetheless, that the observed gests that further escalation would lead to greatly prolonged dose dependency may reflect interindividual variation. myelosuppression requiring the addition of autologous marrow Correlation of clinical and pharmacokinetic indices leads to transplantation. In that setting, Brown et al. (2) and Lazarus et some difficulty in interpreting the importance of the predomi al. (3) have shown that 10-fold higher doses of thioTEPA are nance of TEPA as an alkylating species at low doses. Toxicity tolerable; mucositis and central neurological effects predomi to neutrophils and total WBC was clearly a function of the nate. These side effects were not observed in this study. The AUC, the total clearance, and the dose of thioTEPA in decreas only nonmyelosuppressive effect of note was nausea and vom ing order of importance. No correlation with TEPA kinetics iting which usually responded well to standard treatment. It is was evident. This is somewhat puzzling since in MCF-7 breast worth noting that protracted nausea and malaise (without vom carcinoma cells in culture, TEPA is almost as potent an alkyl iting) occurred in two patients; this could be interpreted as a ating agent as thioTEPA (50% inhibitory AUC for thioTEPA, mild neurotoxic effect. In both instances the patients withdrew 47 MMXh,versus 90 /^MXh for TEPA) (29), and similar results from the study, indicating its potential clinical importance. In have been obtained for P388 leukemia (30). Cohen et al. (13) the majority of patients, however, no symptoms occurred. Of have postulated that additional metabolic steps may be required particular note too was the absence of alopecia in any patient. to generate the alkylating species. Further in vitro studies are Therefore thioTEPA may be an important addition to adjuvant needed to clarify the molecular mechanisms involved in the therapy, especially in breast cancer, where compliance may be cytotoxicity of these agents. adversely affected by toxicity (25). To this end, we are currently Also of concern is the failure of pharmacokinetic indices to conducting a phase II evaluation of a thioTEPA-containing predict decreases in platelet counts, although the grade of combination in breast cancer. platelet toxicity appeared to be a function of dose. This finding Of nine patients with advanced ovarian cancer entered on may suggest that platelet toxicity is to a degree idiosyncratic this study, three responded. All had multiple prior chemother and that it may relate to interindividual differences either in apy regimens, and sites of disease included peritoneal cavity the nature of the lesion produced or in its repair in platelet only, liver only, and chest wall. The toxicity experienced by precursor cells. these patients (grades 2-4) did not distinguish them from The more extensive use of thioTEPA in standard-dose and nonresponders, and their pharmacokinetic parameters for both high-dose regimens has led to increased interest in the phar thioTEPA and TEPA fell within midrange. macology of this alkylator. The higher phase II dose identified The pharmacokinetic analysis of this study revealed several in this study should be evaluated further in alkylator-responsive previously undescribed findings. Of greatest interest was the diseases. The limited extramedullary toxicity from thioTEPA dose-dependent behavior of thioTEPA, the clearance of which makes this drug an excellent candidate for evaluation in com diminished greatly at doses >55 mg/m2. This effect did not bination with colony-stimulating factors. appear to relate to drug distribution since the FÂ¡rfssremained fairly constant with dose. A partial explanation is provided by ACKNOWLEDGMENTS a consideration of TEPA kinetics. The AUC of TEPA did not vary with thioTEPA dose, suggesting that oxidative desulfura- We wish to recognize the dedicated care given by the nurses of the tion is rate limited even at the lowest dose (30 mg/m2) used in Mary S. Schinagl Clinical Pharmacology Unit (1 South); the excellent this study. The kinetics of TEPA formation is the subject of an secretarial assistance of Noreen McCann, Barbara Arrighy, Karen ongoing study. It is important to note, however, that saturation Smith, and Catherine Thompson; and the expert data management of Catherine Janus. of thioTEPA metabolism to TEPA, also identified in a parallel study in children (26), is insufficient to explain the observed dose dependency, which appears only at the highest doses. REFERENCES These data are consistent in part with the observations of 1. Sykes, M., Karnofsky. D.. Phillips. F.. and Burchenal. J. Clinical studies of others. Henner et al. (27) found that the CIT of thioTEPA by triethylenethiophosphoramide and diethylencphosphoramide compounds continuous infusion varied inversely with dose in the range with nitrogen mustard-like activity. Cancer (Phila.). 6: 142-148. 1953. 180-900 mg/m2. Mean plasma clearance (315 ml/min/m2) at 2. Brown. R.. Herzig, R., Fay, J., Wolff. S.. Strandjord. S.. Egorin, M., and Herzig. G. A phase I-I1 study of high-dose W,W,W'-triethylenethiophos the highest dose in our study (75 mg/m2) was close to that phoramide (thiotepa) and autologous marrow transplantation (AMT) for identified at the lowest dose (387 ml/min/m2 at 180-mg/m2 refractory malignancies. Proc. Am. Soc. Clin. Oncol. Annu. Meet., 5: 127, 1986. dose) in that study (data recalculated from Table l in Ref. 27). 3. Lazarus, H. M., Reed, M. D.. Spitzer. T. R.. Rabaa, M. S., and Blumer, J. Egorin et al. (12) and Cohen et al. (13), on the other hand, L. High-dose i.v. thiotepa and cryopreserved autologous bone marrow trans observed much lower AUC for TEPA and did not demonstrate plantation for therapy of refractory cancer. Cancer Treat. Rep., 77:689-695, 1987. saturable kinetics of thioTEPA over the dose range 12-475 4. Wright, J. C., Golomb, F. M., and Gumport. S. L. Summary of results with mg/m2. Unfortunately TEPA levels were followed for only 4 h, triethylenethiophosphoramide. Ann. N.Y. Acad. Sci.. 68: 937-966, 1958. 5. Bateman. J. C.. and Winship. T. Palliation of ovarian cancer with phosphor- which may have greatly underestimated the TEPA AUC in light amide drugs. Surg. Gynecol. Obstet., 102: 347-354. 1956. of its prolonged half-life. Furthermore, while all the patients 6. Hart, R. D., Perloff, M.. and Holland. J. F. Vinblastine, adriamycin. thiotepa, on the study of Henner et al. (27) were treated uniformly with and halotestin (VATH): therapy for advanced breast cancer refractory to prior therapy. Cancer (Phila.). 39: 1289-1293. 1977. concomitant cyclophosphamide, only some of the patients re 7. Hart. R. D.. Perloff. M., and Holland. J. F. One-day VATH (vinblastine. ported by Cohen et al. (13) were thus treated. Since cyclophos adriamycin. thiotepa, and halotestin) therapy for advanced breast cancer 3175

refractory lo chemotherapy. Cancer (Phila.). 48: 1522-1527, 1981. kinet. Biopharm., 71: 445-449. 1982. 8. Phillips, R. M., Bibby. M. C., and Double. J. A. Experimental correlations 20. Egorin, M. J.. Sigman, L. M.. VanEcho, D. A., Forrest, A.. Whitacre, M. of in vitro drug sensitivity with in vivo responses to thiotepa in a panel of Y., and Aisner, J. Phase I clinical and pharmacokinetic study of hexameth- murine colon tumors. Cancer Chemother. Pharmacol., 21: 168-172, 1988. ylene bisacetamide (NSC 95580) administered as a five-day continuous 9. Herzig, R., Brown, R., Fay, J.. Wolff, S., and Herzig, G. High-doseN,N',N"- infusion. Cancer Res., 47: 617-623, 1987. triethylenethiophosphoramide (thiotepa) and autologous marrow transplan 21. Statistical Consultants, Inc. PCNONLIN and NONLIN 84: software for the tation (AMT) for metastatic malignant melanoma (MMM). Proc. Am. Soc. statistical analysis of nonlinear models. Am. Slat., 40: 1, 1986. Clin. Oncol. Annu. Meet.. 5: 126. 1986. 22. Bateman, J. C. Chemotherapy of solid tumors with triethylenethiophosphor- 10. Gorchow, L., Grossman, S.. Garrett, S., et al. Pharmacokinetics of intraven- amide. N. Engl. J. Med., 252: 879-887. 1955. tricular thiotepa in patients with meningeal carcinomatosis. Proc. Am. Soc. 23. Fisher. B.. Redmond. C., Fisher. E. R., and Wolmark, N. Systematic adjuvant Clin. Oncol. Annu. Meet., /: 19. 1982. therapy in treatment of primary operable breast cancer: National Surgical 11. Egorin. M. J., Cohen, B. E.. Kohlhepp, E. A., and Gutierrez, P. L. Gas- Adjuvant Breast and Bowel Project experience. Nati. Cancer Inst. Monogr., liquid Chromatographie analysis of iV,/V',A/"-triethylenethiophosphoramide 7:35-43, 1986. and A',.\",A"'-triethylenephosphoramide in biologic samples. J. Chroma- 24. Friedman, H. S.. Colvin, O. M., Ludman, S. M., Schold, S. C., Boyd, V. L., togr. 343: 196-202, 1985. Mulhbaier, L. H., and Bigner, D. D. Experimental chemotherapy of human 12. Egorin. M. J.. Cohen, B. E., Herzig. R. H.. Ratain, M. J.. and Peters, W. P. medulloblastoma with classical alkylators. Cancer Res., 46: 2827-2833, Human plasma pharmacokinctics and urinary excretion of thiotepa and its 1986. metabolites in patients receiving high-dose thiotepa therapy. In:G. P. Herzig 25. Lebovits. A. H.. Strain. J. J., Schleifer, S. J., Tanaka, J. S., Bhardwaj, S., (ed.). High-dose Thiotepa and Autologous Marrow Transplantation, pp. 3- and Messe, M. R. Patient noncompliance with self-administered chemother 8. New York: Park Row Publishers. 1987. apy. Cancer (Phila.), 65: 17-22. 1990. 13. Cohen, B. E., Egorin. M. J., Kohlepp. E. A., Aisner, J., and Gutierrez, P. L. 26. Heideman, R. L., Cole, D. E., Balis, F., Sato, J., Reaman, G. Hâ€žPacker, R. Human plasma pharmacokinetics and urinary excretion of thiotepa and its J., Singher, L. J., Ettinger, L. J., Gillespie, A.. Sam, J., and Poplack, D. G. metabolites. Cancer Treat. Rep.. 70:859-864. 1986. Phase l and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid 14. Strong. J. M., Collins. J. M.. Lester. C.. and Poplack. D. G. Pharmacoki and plasma of pediatrie patients: evidence for dose-dependent plasma clear netics of intraventricular and intravenous N.N'.N "-triethylenethiophosphor- ance of thiotepa. Cancer Res., 49: 736-741, 1989. amide (thioiepa) in rhesus monkeys and humans. Cancer Res.. 46: 6101- 27. Henner. W. D.. Shea, T. C., Furlong, E. A., Flaherty, M. D., Eder, J. P., 6104, 1986. Elias, A., Begg, C., and Antman, K. Pharmacokinetics of continuous-infusion 15. Miller. A. B., Hoogstraten, B., Staquet. M., and Winkler, A. Reporting high-dose thioTEPA. Cancer Treat Rep., 71: 1043-1047, 1987. results of cancer treatment. Cancer (Phila.), 47: 207-214, 1981. 28. LaCreta, F. P., Tinsley. P. W., and O'Dwyer, P. J. Dose dependent elimi 16. Knot!. G. D. M LABâ€”a mathematical modeling tool. Comput. Programs nation of thioTEPA by the isolated perfused rat liver. Proc. Am. Assoc. Biomed., 10: 271-280. 1979. Cancer Res., 31: 386. 1990. 17. Yamaoka. K., Nakagawa. T., and Uno. T. Application of Akaike's informa 29. Cole. D. E., Johnson, G., Tartaglia, R. L., O'Dwyer. P.. Balis, F., and tion criterion (AIC) in the evaluation of linear pharmacokinetics equations. Poplack. D. G. Correlation between plasma pharmacokinetics and in vitro J. Pharmacokinet. Biopharm.. 6: 165-175. 1978. cytotoxicity of thiotepa and TEPA. Proc. Am. Soc. Clin. Oncol. Annu. 18. Gibaldi. M., and Perrier, D. Pharmacokinetics, Ed. 2. New York: Marcel Meet., 8: 72. 1989. Dekker, Inc., 1982. 30. Miller, B., Tenenholz, T., Egorin, M. J., Sosnovsky, G., Rao, N. LI. M., and 19. Perrier, D.. and Meyershon. M. Noncompartmental determination of steady Gutierrez, P. Cellular pharmacology of A'.yV'./V'-triethylenethiophosphor- state volume of distribution for any mode of administration. J. Pharmaco amide. Cancer Lett., 41: 157-168, 1988.

3176

Peter J. O'Dwyer, Frank LaCreta, Paul F. Engstrom, et al.

Cancer Res 1991;51:3171-3176.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/51/12/3171

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/51/12/3171. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.