pharmacokinetic studies

Annals of Oncology 1: 217-221, 1991. O 1991 Kluwer Academic Publishers. Printed in the Netheriands.

Original article Teniposide and cisplatin given by intraperitoneal administration: Preclinical and phase I/pharmacokinetic studies E. Chatelut,1 M. de Forni,1-2 P. Canal,1-4 C. Chevreau,1 H. Roche,1 Y. Plusquellec,2-4 N. P. Johnson,3 G. Houin1-2-4 & R. Bugat1-2 1

Unite de Pharmacologie et de Pharmacocinetique Cliniques, Centre Claudius Regaud, Toulouse France; 2 Universite Paul Sabatier, Toulouse, France; 3CNRS U201, Toulouse, France; *Centre Interdisciplinaire d'Etudes Pharmacocinetiques de Toulouse (CINET), Toulouse, France

Summary. Cisplatin and teniposide given by intraperitoneal (IP) route exert a synergistic therapeutic effect against ascitic P388 leukemia in mice. As single agents, they display different dose-limiting toxicities and favourable pharmacokinetic characteristics in IP phase I trials. We administered cisplatin (fixed dose: 200 mg/m2) and teniposide (escalating doses) by IP route without dwell-time to investigate the toxicity, pharmacokinetics and clinical activity of this 2-drug combination. Nine patients received a total of 14 courses. Myelosuppression, nausea and vomiting were the most frequent toxicities. Leukopenia was the dose-limiting toxicity. The maximum tolerated dose of teniposide was 100 mg/m2 when administered with a fixed dose of 200 mg/m2 cisplatin. Pharmacokinetic analysis showed that the main parameters of both cisplatin and teniposide in the peritoneum and in the plasma were not modified when the drugs were combined. It appears that a pharmacodynamic interaction exists between cisplatin and teniposide which results in increased hematologic toxicity. Although an objective response has been observed in one patient with refractory ovarian cancer, such association should not be applicable for further clinical development due to marked toxicity and the low dose of teniposide recommended.

Introduction Cis-diammine-dichloroplatinum (II) (CDDP) is the most active drug currently used by intraperitoneal route (IP) in the treatment of ovarian cancer [1,2]. Since in vivo studies [3] on mice have shown that the antitumoral activity of CDDP may be enhanced when combined with etoposide, 5FU, melphalan or aracytine, clinical trials have been undertaken, using CDDP administered by IP route with other drugs, to increase its activity [4,5]. In a previous phase I trial [6], we reported the feasibility of IP administration of teniposide - an analogue of etoposide - and determined, in humans, its maximum tolerated dose (MTD) of 450 mg/m2 as single agent - with a 4-hour dwell-time. After demonstrating an in vivo synergistic activity between CDDP and teniposide on the P388 leukemia model, a phase I trial was undertaken to establish the MTD of IP teniposide combined with 200 mg/m2 CDDP and concomitant intravenous administration of sodium thiosulfate (16 g/m2). The IP administration was carried out in this trial without any dwell-time since it has been established that it is not necessary to drain the peritoneum of CDDP due to its peritoneal pharmacokinetics [7,8]. On the other hand, our previous study [6] snowed that only half of a teniposide dose is absorbed with a 4-hour dwell-time. Finally, this route of administration has been adopted taking into

account the difficulty of drainage due to catheter problems [9]. The pharmacokinetics of both CDDP and teniposide have been studied in plasma and peritoneum. The decay kinetics have been fitted with a previously published open three compartment model [10]. Preclinical study Material and methods 10-week-old B 6 D 2 Fi/Flco mice, weighing 20-25 g, were injected intraperitoneally with 106 P388 leukemic cells on day 0, and were treated with cisplatin and etoposide or teniposide given ip once, 24 hours after tumor inoculation. The efficiency of the different treatments was estimated by the percent of increase in life span of treated versus control groups. The long-term mice survivors were scored on day 60 post-inoculation. Results As shown in Fig. 1, no antagonism was found between cisplatin and epipodophyllotoxins when the drugs were tested together against P388 leukemia. When cisplatin and etoposide or teniposide were administered 24

218

VP16+C0DP VM26+CDDP VP16 VM26 CDDP Control* 0

20

40

60

60

Days after tumor Inoculation

Fig. I. Preclinical results: Comparison of antitumoral activity of CDDP (6 mg/kg) combined with either etoposide (6 mg/kg) or teniposide (1.5 mg/kg) on mice bearing P388 leukemia transplanted one day before drug treatment.

hours after tumor inoculation, a great increase in life span (>500%) of treated animals versus controls was observed. Rates of 60% (etoposide) and 75% (teniposide) long-term survivors were noted, suggesting equivalent potentiations of both epipodophyllotoxin and cisplatin. Clinical study Material and methods Patient selection Entry criteria included histologically-proven tumor with abdominal carcinomatosis and/or malignant ascites refractory to conventional modes of therapy. Patients were required to have a life expectancy greater than 9 weeks, a WHO performance status level 3 or better, serum creatinine level less than 130 u.mol/1, bilirubin level less than 20 nmol/1, leukocyte and platelet counts greater than 3000/mm 3 and 100 000/mm 3 , respectively, and to be between 18 and 70 years of age. All patients had a surgically placed peritoneal catheter. On the day before the treatment, an abdominal scintigraphy was performed with 3mCi of 99mTechnetium microaggregated albumin to assess the adequacy of fluid distribution throughout the peritoneal cavity. Written informed consent was obtained from the patients before entry into the study. The protocol had previously been approved by the local Ethical Committee. Determination of the starting dose and escalating scheme Patients received a fixed dose of CDDP: 200 mg/m2. The starting dose of teniposide was determined on the basis of the previous phase I study of intraperitoneal administration of this drug in monochemotherapy with a 4-h dwell-time [6]. At the maximum tolerated dose of 450 mg/m2, only 253 ± 6 9 mg/m2 of teniposide had been absorbed and was thus responsible for the hematologic toxicity observed. Therefore, the M I D of teniposide in monochemotherapy without dwell-time was estimated to be near 250 mg/m2. On this basis, the ini-

tial teniposide dose level was fixed at 100 mg/m2 in the present study. Step dose increments of 50 mg/m2 were planned unless unacceptable toxicity occurred. At least three patients had to be treated at each teniposide dose level. MTD was defined as the dose inducing a WHO grade 3 toxicity in more than 50% of patients. No intrapatient dose escalation was allowed. Treatment was repeated every 4 weeks providing there was no residual toxicity. Treatment plan Prehydration by IV route with 2 liters of 0.9% sodium chloride with 8 meq KCI and 4g MgSO4 was given for 12 hours before IP drug administration. Also, 500 ml of macromolecules (DextranR, Roger Bellon Laboratories) were administered IV over 30 min. before IP administration. The required dose of teniposide and 200 mg/m2 cisplatin were mixed together in 2 liters of 0.9% sodium chloride solution and administered during 2 hours into the abdominal cavity through a Tenckhoff catheter (N = 7) or a Port-a-Cath system (N - 2). In no case, was the peritoneal dialysat drained. At the initiation of the chemotherapy, 4 g/m2 of sodium thiosulfate in 250 ml of sterile water was administered IV over 10 minutes, immediately followed by a thiosulfate IV infusion of 2 g/m2/h for 6 h. The treatment was completed with the administration of 2 liters of 0.9% sodium chloride solution over a 24-h period. All patients received vigourous supportive antiemetic therapy consisting of high-dose metoclopramide and lorazepam. The protocol required baseline and follow-up laboratory studies including complete blood counts, platelet counts, serum creatinine measurements and liver function studies at 2 and 4 days and weekly thereafter for 3 weeks. WHO criteria for toxicity and response were used. Cisplatin and teniposide assays Pharmacokinetics were performed during the first cycle only. To measure teniposide and cisplatin concentrations, peritoneal fluid obtained through the catheter was sampled in dry tubes as follows: at the end of the infusion and 15, and 30 min, and 1, 2, 3, 4, 6, 10, 12, 18, 24 and 48 h after the end of infusion. Plasma samples were obtained in heparinized tubes at the same times and at 40 and 80 min after the beginning of infusion. Immediately after sampling, the plasma was separated by centrifugation. Separation of unbound platinum from total platinum in plasma and peritoneal fluid was carried out by ultrafiltration through Amicon Centrifee MPS1 system with YMT membranes at 4 °C. Samples for teniposide and ultrafilterable platinum were stored at - 2 0 *C until analysis. Platinum concentrations were determined by flameless atomic absorption spectrophotometry. Teniposide levels were assayed by high-performance liquid chromatography as described by CANAL et al [11].

219 Pharmacokinetic analysis The data obtained for peritoneal and plasma ultrafilterable platinum and teniposide were fitted separately using the Siphar computer program. The areas under the curve were calculated by trapezoidal rule and extrapolated to infinity. The peritoneal clearance was calculated by the following formula: CI = Dose/AUC (area under the curve). Finally, the peritoneal and plasma teniposide concentrations were fitted together using the open three compartment model previously described [10]. Student test was used for statistical analysis and correlation analysis (r test) was performed between teniposide plasmatic AUC and leukocytes, granulocytes or platelets nadir counts. Results Patients 9 patients (6 women and 3 men) ranging in age from 47 to 66 years (median 62) with refractory intraperitoneal tumors entered the study. They were suffering from advanced ovarian carcinoma [4], digestive carcinoma [2], soft tissue sarcoma [2], or breast cancer [1]. In all cases, recurrent IP tumor consisted of macroscopic disease with either bulky tumor [6] or residual disease greater than 1 centimeter in diameter [3]. Seven patients had previously received chemotherapy, with 4 of these regimens containing cisplatin. The total dose of CDDP previously received ranged from 360 to 600 mg/m2 (median 500 mg/m2). Two patients had received previous abdominal radiotherapy. Table I. Hematologic toxicity according to teniposide dose. nadir (1071)

Granulo- Platelets Hemonadir globin* cytes nadir (1071) (1071)

5.59 1.60 1.10 5.70 0.70

3.79 0.80 0.77 3.99 0.20

5.90

2.58 1.40 3.70 2.40

WBC

100 mg/m2

First cycle Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Other cycle Patient 4 C2

50 mg/m2

167 10 259 100

24.1 21.8 25.4 14.3 24.1

4.13

175

9.1

1.46 0.84 1.55 0.84

245 84

25.6 37.3 26.7 12.8

N.E.

First cycle Patient 6 Patient 7 Patient 8 Patient 9 Other cycle Patient 5 C2 C3 Patient 6 C2 C3

3.40 1.19 1.93 2.00

* % of decrease of hemoglobin pretreatment.

Toxicities At 100 mg/m2 teniposide dose level (5 patients, 6 cycles), leukopenia was the prominent and dose-limiting side effect: analysis of the first cycle of chemotherapy revealed that 3 of 5 patients experienced a WHO grade 3-4 granulocyte toxicity (Table 1). One patient, suffering from extensive Brenner tumor, developed an early syndrome (day 2) of polyvisceral failure including severe myelosuppression (grade 3 leukopenia and grade 4 thrombocytopenia), gastrointestinal bleeding, renal failure (creatinine level: 370 (imol/1) and subsequently irreversible collapse leading to death on day 11. This early death was considered to be drug related. Because of this unacceptable toxicity observed at 100 mg/m2 the dose of teniposide was reduced by 50%. At 50 mg/m2 teniposide dose level (5 patients, 4 of them previously untreated with teniposide, 8 courses), once again, leukopenia was the principal but acceptable toxicity since it resulted in only two grade 3 s among the four evaluable courses administered as first cycle. Non-hematologic side effects included digestive toxicity (nausea and vomiting grade 2-3, diarrhea grade 2 which responded to supportive therapy), and local toxicity (mild to moderate abdominal pain which did not require analgesic medication during or after drug administration). Except for the patient who died, there were no cases of cisplatin-induced nephrotoxicity, probably because of the prehydration and sodium thiosulfate regimen. However, in the first week following drug administration, there was a transient rise in serum creatinine level which was reversible in 4 to 11 days. In all patients, the creatinine value returned to normal under intensive and prolonged hydration. Response Five patients who received 2 cycles of IP chemotherapy or more were evaluable for response. An objective response was observed in one patient suffering from ovarian carcinoma refractory to a standard cisplatincontaining regimen (macroscopic disease at second look laparotomy). The response was documented by a third laparotomy for catheter removal. This patient is alive and free of disease at 5 months after the thirdlook procedure. For the other patients, the median time to progression was 8 weeks and death occurred between 1.5 and 20 weeks (median: 13.5 weeks) after therapy completion.

Pharmacokinetics There were no dose-dependent pharmacokinetics as indicated by the absence of significant differences in 2.40 90 39.6 peritoneal and plasma clearances. The peritoneal and 0.65 81 28 plasma maximum concentrations were two times 1.10 279 0 higher at 100 mg/m2 than at 50 mg/m2. Figure 2 illus1.14 205 0 trates the mean peritoneal (N •» 7) and plasma (N = 9) levels at nadir in comparison with concentrations of teniposide. The values for major pharmacokinetic parameters are shown in Table 2. The 86

47

220 Table 3. Pharmacokinetic parameters of ultrafilterable platinum after IP administration.

H.ASHA

Parameters Peritoneal peak concentration (mg/l) Peritoneal half-life (h range) Peritoneal AUC (mg/lxh) Peritoneal clearance (1/h/m2) Plasma peak concentration (mg/l) T max (h) TIME Ik) Plasma elimination half-life Fig. 2. Mean of peritoneal and plasma teniposide concentrations in (h) patients after IP administration of 50 (+) or 100 mg/m2 (•). Peri- Plasma AUC (mg/lxh) toneal concentrations. Plasma concentrations. Model analysis. Plasma clearance (1/h/m2) Points: mean. Bars: SD. Peritoneal/plasma (peak ratio) Peritoneal/plasma (AUC ratio)

Values 36.1 ±13.2 1.66 (0.82-3.97) 108.9 ±55.7 1.53± 0.73 1.99 ± 0.42 2.3 (2-4) 3.91 (2.51-10.3) 15.77± 6.48 9.69 ± 3.70 20.6 ±12.5 8.8 ± 6.3

peritoneal concentrations declined monoexponentially in three patients with a mean half-life of 9.7 h (8.3-13 h) and biexponentially in the four others (Tl/2a: 2 h (1-4.5 h), T1/2P: 21.9 h (17.4-31.2)). In plasma, the time to achievement of the maximum concentration of teniposide ranged between 5 and 14 h (mean: 7.2 h). The plasmatic concentrations declined monoexponentially with a mean half-life of 16.6 h. No correlation was observed between teniposide plasma AUC and leukocytes, granulocytes or platelets nadir counts. The peritoneal and plasma pharmacokinetic parameters of ultrafilterable platinum are summarized in Table 3.

further improve the demonstrated efficacy of this drug [1,2]. For this study, teniposide was selected for use in combination with cisplatin because of its excellent synergistic effect with CDDP in the P388 leukemia model in vivo, its pharmacokinetic parameters and safe administration by IP route [6,12]. In this study, we have found that the MTD (defined as the dose inducing a grade 3-4 toxicity in more than 50% of patients) of teniposide reached 100 mg/m2 when given by intraperitoneal route without dwell-time and combined with high-dose cisplatin (200 mg/m2). Neutropenia was the dose-limiting toxicity (60% of grade 3-4 toxicity). A similar but less severe toxic profile was encountered at 50 mg/m2 teniposide dose level, which could be the recommended dose of teniposide when combined with high-dose cisplatin. The MTD was lower than expected. In a previous phase I Discussion study investigating teniposide given IP as a single agent 2 Numerous intraperitoneal trials for ovarian carcinoma [6], the MTD reached 450 mg/m when the perihave attempted to identify a clinically active agent that toneum was drained 4 hours later. On the basis of the could be used in combination with IP cisplatin to amount of drug recovered in the drained fluid, the dose responsible for hematologjc toxicity was estimated to be near 250 mg/m2. When comparing the teniposide Table 2. Pharmacokinetic parameters of teniposide after IP adminplasmatic AUC obtained at the MTD in our two istration. studies, this parameter was found to be lower without 50 mg/m2 100 mg/m drug drainage than with drainage (115 ± 33 vs 158 ± 70 mg/lxh). Consequently, the lack of drug drainage might Peritoneal clearance 108 ± 51 104 ± 32 have increased the myelosuppression induced by the 2 ml/h/m two-drug combination, but it can not completely exPeritoneal Cmax 33.5 ± 7.8 58.5 ± 15.9 plain the discrepancy between the predicted and ob(mg/l) Peritoneal AUC 658 ±407 1051 ±318 served teniposide MTD.

mg/lxh Plasma Cmax mg/l Plasma elimination T 1/2 (h) Plasma AUC mg/lxh Plasma clearance ml/h/m 2 Peritoneal/plasma Cmax ratio Peritoneal/plasma AUC ratio

2.25 ±

65.4 ± 765

0.83

3.34 ±

16.6 (9.4-48.7) 3.9 115

± 47

962 22.7± 11.3 10.5± 5.4

1.37

±33 ±331

The pharmacokinetics data of cisplatin generated in 9 patients are similar to those obtained by Howell et al. [7]. The peritoneal half-life and the clearance of ultrafilterable platinum were in the same range. Cisplatin given at 200 mg/m2 produced an AUC for peritoneum that was 10 times greater than that for the plasma. For teniposide, the peritoneal clearance was on the same order of magnitude as that obtained in monochemotherapy with a 4 h dwell-time [6]: 105 ± 41 ml/h/ m2 vs 131 ±75 ml/h/m2. However, in some patients, we noticed a biphasic disappearance of teniposide

221 from the peritoneum. In plasma, the teniposide clear- 2. Howell SB, Kirmani S, Lucas WE, Zimm S, Goel R, Kim S, Horton MC, McVey L, Morris J, Weiss RJ. A phase II trial of ance and AUC were similar to those obtained after intraperitoneal cisplatin and etoposide for primary treatment intravenous administration of this drug at a 100 mg/m2 of ovarian epithelial cancer. J Clin Oncol 1990; 8: 137-45. dose level [13]. Despite the high variability of pharma- 3. Schabel FM Jr, Trader MW, Laster WR Jr et al. Cis-dischlorocokinetic parameters, the plasmatic AUC was two-fold diammineplatinum (11): combination chemotherapy and crosshigher at 100 than at 50 mg/m2, but no relationship has resistance studies with tumors of mice. Cancer Treat Rep 1979; 63:1459-73. been observed with the hematologic toxicity. No significant differences were observed between 4. Zimm S, Cleary SM, Lucas WE et al. Phase I/pharmacokinetic study of intraperitoneal cisplatin and etoposide. Cancer Res the pharmacokinetic parameters of either cisplatin or 1987; 47:1712-6. teniposide, and those obtained in monochemotherapy. 5. Piccart MI, Abrams J, Dodion PF et al. Intraperitoneal chemoNevertheless, the hematologic toxicity obtained with therapy with cisplatin and melphalan. J Natl Cancer Inst 1988; 80:1118-24. combined chemotherapy was more pronounced than 6. Canal P, Bugat R, Chatelut E et al. Phase I/pharmacokinetic that obtained with teniposide alone. Our results suggest study of intraperitoneal teniposide (TENIPOSIDE). Eur J that a pharmacodynamic interaction exists between Cancer Clin Oncol 1989; 25: 815-20. CDDP and teniposide, resulting in increased hemato7. Howell SB, Pfeifle CG, Wung WE et al. Intraperitoneal cislogic toxicity, irrespective of the effect of sodium thioplatin with systemic thiosulfate protection. Ann Intern Med 1982; 97: 845-51. sulfate on cisplatin efficacy or toxicity [14,15]. The same interaction might explain the differences in eto- 8. Canal P, Chatelut E, De Forni M et al. Pharmacocinetique du cisplatine apres administration intraperitoneale a 2 doses: 100 poside MTD when given in monochemotherapy by IP ou 200 mg/m2. Bull Cancer (Paris) 1989; 76: 879-82. 2 route (800 mg/m ) [16] or in combination with high- 9. Piccart M, Speyer J, Markmann M et al. Intraperitoneal dose cisplatin (350 mg/m2) [1]. chemotherapy: technical experience at five institutions. Sem Oncol 1985; 12 (suppl 3}. 90-6. Although feasible, the IP teniposide - cisplatin com10. Canal P, Plusquellec Y, Chatelut E et al. A pharmacokinetic bination tested in this study is probably precluded from model for intraperitoneal administration of drugs: application further clinical development due to marked toxicity to teniposide in humans. J Pharm Sci 1989; 78: 389-92. and to low teniposide dose contribution. Nevertheless, 11. Canal P, Michel C, Bugat R et al. Quantification of teniposide it is noteworthy that teniposide and etoposide have in human serum by high-performance liquid chromatography with electrochemical detection. J Chromatogr 1986; 375: 451 — shown quite similar properties when associated with 6. cisplatin by IP route in terms of preclinical and phar12. Canal P, Bugat R, Rokoszak B et al. Pharmacokinetics and effimacokinetic behaviours. 13.

Acknowledgements

The help and the cooperation of the nursing staff of the 'Unite de Pharmacologie Clinique' is greatly appreciated. This work was supported by a grant from the 'Federation Nationale des Centres de Lutte Contre le Cancer'. The author thank Dr Montana (Duke University) for reviewing the manuscript

14. 15. 16.

cacy of ip and iv VM 26 chemotherapy in mice bearing Krebs II ascitic tumors. Eur J Cancer Clin Oncol 1986; 22: 765-71. D'lncalci M, Rossi C, Sessa C et al. Pharmacokinetics of teniposide in patients with ovarian cancer. Cancer Treat Rep 1985; 69: 73-7. Howell SB, Taetle R. The effect of sodium thiosulfate on cisdichlorodiammineplatinum (II) toxicity and antitumor activity in the L1210 leukemia. Cancer Treat Rep 1980; 64: 611-6. Howell SB, Pfeifle CG, Wung WE, Olshen RA. Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection. Cancer Res 1983; 43: 1426-31. Daugherty JP, Lacreta FP, Gibson N et al. Phase I study of intraperitoneal etoposide (VP 16). Proc Am Soc Clin Oncol 1987;6:32(abstr).

Received 28 May 1990; accepted 18 September 1990.

References 1. Howell SB, Zimm S, Markman M et al. Long-term survival of advanced refractory ovarian carcinoma patients with smallvolume disease treated with intraperitoneal chemotherapy. J Clin Oncol 1987; 5: 1607-12.

Correspondence to: P. Canal, M.D. Centre Claudius Regaud 20-24 Rue du Pont Saint-Pierre, 31052 Toulouse Cedex, France

Aruialsqf Oncology 2: 222,1991.

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