Phase I study of daily times five topotecan and single injection of cisplatin in patients with previously untreated non-small-cell lung carcinoma

Annals of Oncology 8: 1003-1008, 1997. O 1997 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Phase I study of daily times five topotecan and single injection of cisplatin in patients with previously untreated non-small-cell lung carcinoma E. Raymond,1 H. A. Burris,2 E. K. Rowinsky,1 J. R. Eckardt,1 G. Rodriguez,1 L. Smith,3 G.Weiss3 & D. D.Von Hoffl 1

Cancer Therapy and Research Center. 2Brooke Army Medical Center, 3 University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

Summary Background: The objectives were to determine the dose-limiting toxicity of topotecan in combination with cisplatin, to describe the principal toxicities, and to define the maximallytolerated doses of the drugs in previously untreated patients with advanced non-small-cell lung carcinoma. Patients and methods: The study was designed to evaluate escalated doses of topotecan (starting at 0.75 mg/m 2 /day) as a 30-minute infusion daily for five consecutive days with a fixed clinically-relevant dose of 75 mg/m 2 cisplatin given on day 1, every three weeks. Results: Fifteen chemotherapy-naive patients entered the study and 14 were evaluable for toxicity. All 11 patients treated at the first topotecan/cisplatin dose level of 0.75/75 mg/m 2 , experienced at least one episode of grade 4 neutropenia. For six patients, absolute neutrophil counts were below 500/ml for more than five days, and two of them developed a grade 4 thrombocytopenia. At the next higher topotecan/cisplatin dose level (1.0/75 mg/m 2 ), grade 4 neutropenia lasting longer

Introduction

Topotecan (TPT; 9-dimethylaminomethyl-10-hydroxycamptothecin), a semi-synthetic water-soluble analog of camptothecin [1, 2], reversibly inhibits topoisomerase I, a cellular enzyme that is involved in maintaining the topology of DNA [3]. Treatment with camptothecin analogs results in the formation of topoisomerase I-DNA adducts that collide with the advancing DNA replication forks during DNA synthesis [4], thereby producing irreversible DNA double-strand breaks [5] and eventually inducing cell death [6]. Although the precise mechanisms of TPT's cytotoxicity remain unclear, this drug has demonstrated considerable activity against human cancer as a single agent both in mice bearing human tumor xenografts [7] and in a human tumor cloning assay [8]. The ability of camptothecin analogs to form reversible topoisomerase I-DNA complexes suggests that TPT might possibly interfere with processes involved in the formation and repair of DNA lesions induced by several

than five days occurred in all three evaluable patients, including one patient who expired due to a severe neutropenia associated with sepsis. Non-hematologic toxicities, predominantly nausea and vomiting, were mild to moderate in severity and manageable. Four patients had partial responses (30.7%; 95% confidence interval (9%-61%) of relatively short duration. Conclusion: Both severe neutropenia and thrombocytopenia precluded dose escalation of topotecan and cisplatin administered on this schedule. In previously untreated patients, the first topotecan/cisplatin dose level (0.75/75 mg/m 2 ), was associated with intolerable myelosuppression, and, therefore, the dose levels evaluated in this study cannot be recommended for subsequent phase II investigations. The high toxicity of this schedule and the recent understanding of the pharmacokinetic interaction between those drugs may encourage the investigation of the alternate sequence of cisplatin after TPT in phase II studies. Key words: camptothecin derivative, cisplatin, combination chemotherapy, platinum salts, topotecan, toxicity

alkylating agents such as cisplatin [9-12]. Although recent results indicate that both the cancer cell type and the schedule of administration of TPT and cisplatin are essential for determining their cytotoxic effects, the combination has demonstrated synergistic activity in a number of cancer cell lines and human tumor xenografts [9, 10, 12, 13]. This warranted further clinical investigations in malignancies, such as non-small-cell lung carcinomas, in which both TPT and cisplatin are highly effective. Previous reports have indicated that TPT has manageable toxicity and prominent clinical anticancer activity alone when administered as a 30-minute infusion daily for five days every three weeks [14-16]. In combination with several classical anticancer agents, cisplatin at a dose of 75 mg/m2 every three weeks is a major drug in the treatment of non-small-cell lung carcinoma. When this study was initiated, results of preclinical studies showed that both drugs could be combined safely at near their maximum tolerated dose (MTD) in mice. Therefore, we initiated a phase I trial to determine the MTD and to describe the toxicity of TPT as a 30-minute

1004 infusion daily for five days in combination with a fixeddose of 75 mg/m 2 cisplatin, every three weeks, in previously untreated patients with non-small-cell lung carcinomas.

Patients and methods Eligibility Patients with histologically-documented stage III or IV non-small-cell lung carcinoma, who were not amenable to local radiation therapy or surgery, were candidates for this study. Eligibility criteria also included: 1) age 5 18 years; 2) a Zubrod/WHO performance status ^ 2 (capable of self-care); 3) a life-expectancy & 3 months (enabling the completion of at least two courses of treatment); 4) no prior chemotherapy; 5) no surgery within two weeks or radiotherapy and/or biologic therapy within four weeks of entering onto protocol; 6) adequate hematopoietic (WBC count >4,000/u], absolute neutrophil count (ANQ > 1,500/nl, hemoglobin >9.0 g/dl, and platelet count > 100,000/ul), hepatic (total bilinibin ^ 2.0 mg/dl; SGOT $ 2 times the upper limit of normal (ULN) or $ 3 times ULN in the presence of liver metastases, or alkaline phosphatase < 2 times ULN or < 5 times ULN with liver or bony metastases), and renal (serum creatinine s£ 1.5 mg/dl and a creatinine clearance estimated using the Cockcroft equation with correction for body surface area >60 ml/min) functions; 7) no concurrent medical problem unrelated to the malignancy and/or no coexisting infection which would significantly limit compliance with the study or expose the patient to undue risk; and 8) no brain or leptomeningeal metastases. Before treatment, all patients gave written informed consent, according to federal and institutional guidelines.

uric acid, alkaline phosphatase, total bilirubin, SGOT, SGPT), and urinalysis. When a patient experienced grade 3 and 4 neutropenia, the determination of hematologic parameters was recommended daily until the recovery of an ANC > 1,500/ul and a platelet count > 100,000/ul. The creatinine clearance was recalculated once weekly using the Crockroft-Gault equation. An electrocardiogram was obtained pretreatment and before each course. Audiometnc analysis was obtained pretreatment. Formal tumor measurements were performed after two courses, and patients were able to continue treatment if they did not develop progressive disease. A complete response was defined as the disappearance of all active disease on two measurements separated by a minimum period of three weeks. A partial response required a 50% or greater reduction in the sum of the product of the bidimensional measurements of all measurable lesions documented by two measurements separated by at least three weeks. Disease progression was defined as greater than a 25% increase in the sum of the products of measurable lesions, appearance of any new tumor lesions, or reappearance of lesions.

Procedure for dose escalation

Patients were treated at each dose level and observed for toxic manifestations for at least three weeks before additional patients were treated. Toxicity was graded using the NCI Common Toxicity Criteria. Dose limiting-toxicity (DLT) was defined as: 1) grade 4 neutropenia (ANC < 500/ml) lasting >fivedays or associated with fever requiring hospitalization for parenteral antibiotics, 2) grade 4 thrombocytopenia, and 3) grade 3 non-hematological toxicity, excluding nausea/ vomiting or limited maculopapular rash. Dose escalation proceeded according to the following schema. If one of the initial three patients treated at any dose level experienced DLT, then a maximum of three additional patients were treated at that dose. If no further instances of DLT occurred in the three additional patients, TPT dose escalation resumed. If two new patients experienced DLT, then no further dose escalation was performed. The recommended phase II dose was deTreatment fined as the highest dose at which less than two of six patients This phase I study was designed to evaluate the feasibility of adminis- experienced DLT. Intraindividual dose escalation was permitted, if tered a clinically-relevant fixed dose of cisplatin, 75 mg/m2 as an 1 mg/ patients experienced no toxicity during their first two courses. TPT min intravenous infusion on day 1, with escalating doses of TPT doses were reduced by one level in patients experiencing DLT accordstarting at a dose of 0.75 mg/m2 administered as a 30-minute infusion ing to the following decremental dose levels: 1.0, 0.75, 0.60, and 2 daily forfiveconsecutive days every three weeks. This starting dose of 0.50 mg/m /day. TPT was selected because it was associated with minimal toxicity when TPT was administered as a single agent [7, 15]. All patients were admitted for hydration which consisted of 2 liters of 5% dextrose normal saline solution infused over 12 hours. Prior to cisplatin, TPT Results was administered intravenously over 30 min. Ninety minutes later, cisplatin was administered as a 1 mg/min infusion, preceded by intra- Patient characteristics venous dexamethasone 20 mg and ondansetron 32 mg for prophylaxis of nausea and vomiting. Following cisplatin, hydration was continued Fifteen patients with non-small-cell lung cancer received and ondansetron was repeated at a dose of 8 mg orally every eight hours if necessary. On days 2-5, TPT was administered in the out- a total of 37 courses at planned dose levels of TPT and patient clinic. The treatment course was repeated as long as there cisplatin. Relevant patient characteristics are listed in was no evidence of tumor progression and the following criteria were Table 1. Thirty-seven courses were evaluable, and 14 met: 1) ANC >l,500/ul, 2) platelets 5* 100,000/ul, 3) hemoglobin patients were assessable for toxicity (one patient died of > 9.0 g/dl, and 4) toxicity resolved. rapid progressive disease early during the first course of TPT was provided by SmithKJine Beecham (Conshohocken, PA) in chemotherapy and was not evaluable for toxicity). The vials containing 5 mg of lyophihzed drug as light yellow cake. The vials were stored at 5°C in the dark. The lyophilized formulation was median number of courses administered per patient was reconstituted with 2 ml of sterile water prior to dilution. The mixture three (range 1-8). was finally diluted with 5% dextrose for injection to obtain concenOnly one episode of hematologic dose-limiting toxtrations between 20-100 ng/ml. icity was initially observed in the first six patients enrolled in the first dose level. Four patients were therefore enrolled in the second dose level. One of them, experiPretreatment and follow-up studies enced an unexpected rapid progression of his maligHistories and physical examinations were performed pretreatment and nancy and was not fully evaluable for toxicity. The three weekly. Laboratory studies were performed pretreatment and weekly. subsequent patients entered in the second dose level Routine laboratory studies included a complete blood cell count with a differential WBC, platelet count, chemistries (electrolytes, BUN, crea- experienced hematologic dose limiting toxicity and, tinine, glucose, total protein, albumin, calcium, phosphate, magnesium, therefore, no further dose escalation was performed. To

1005 (39%). Grade 4 thrombocytopenia was observed in two courses. The nadir of neutropenia (ANC < 500/mm3) typically occurred on day 16 (range 10-18). The nadir of platelet count (platelet count < 50,000/ mm3) typically occurred on day 14 (range 8-17). Anemia was mild and infrequent, with a total of only six episodes (11%) of grade 3 anemia registered at the end of thejstudy at the first dose level. Four patients were treated with TPT/cisplatin at doses of 1.0/75 mg/m2. One patient died 13 days after the first course of chemotherapy due to unexpected progression of lung metastases and was not fully evaluable for toxicity. Three subsequent patients experienced grade 4 neutropenia lasting more than five days including one patient who expired due to pseudomonas aeruginosa sepsis associated with grade 3 thrombocytopenia, grade 3 diarrhea, grade 2 hypotension, and grade 2 hypokalemia by day 11 after the first course of therapy. At this dose level, the dose-limiting neutropenia typically occurred on day 10 (range 8-11). Two patients treated at this dose level experienced a concomitant grade 4 thrombocytopenia on day 12 of treatment. Since all the patients experienced a DLT, no further dose escalation was performed.

Table 1 Patient characteristics. Number of patients Gender (male: female) Median age, years (range) Performance status Zubrod/WHO 0 1 -2 Pathology Squamous cell carcinoma Adenocarcinoma Large cell carcinoma Poorly differentiated carcinoma Stage III IV Previous local therapy Surgery Radiotherapy Mean interval between diagnosis and date of entrance onto the study, days (range)

15 14:1 59 (46-77) 8 6

2 11 1 1 3 12 4 4 76(10-181)

Abbreviation: WHO - World Health Organisation.

ascertain whether there was cumulative toxicity after repeated doses of the topotecan/cisplatin combination at the first dose level, additional patients were subsequently enrolled. The study was terminated due to the occurrence with time of dose-limiting toxicity in six among 11 patients enrolled in the fist dose level.

Hematologic toxicity observed at reduced dose levels Four patients received a total of 11 courses of the TPT/ cisplatin combination at reduced doses of 0.60/75 mg/m2 due to prior hematological toxicity at higher dose levels. All of them (eight of 11 courses) experienced at least one episode of grade 4 neutropenia associated with grade 4 thrombocytopenia, and two patients subsequently required TPT dose reductions to 0.5 mg/m2.

Hematologic toxicity observed at planned dose levels Neutropenia and thrombocytopenia were the principal DLTs of TPT and cisplatin on this schedule of administration (Table 2). All 11 patients treated at the first topotecan/cisplatin dose level of 0.75/75 mg/m2, experienced at least one episode of grade 4 neutropenia. For six patients, absolute neutrophil counts were below 500/ml for longer than five days, and two of them developed a grade 4 thrombocytopenia. One patient experienced a grade 3 fever associated with an ANC of 210/mm3 on day 13 of his fourth course of chemotherapy which required the injection of parenteral antibiotics for six days. Two patients also developed grade 3 anemia. Of 33 total courses at this dose level, 23 (70%) were associated with grade 4 neutropenia and ANC < 500 /ml for longer than five days occurred during 13 courses

Non-hematologic toxicity Non-hematologic toxicity was infrequent and mild to moderate. Grade 3 nausea and vomiting were observed in one patient treated with TPT/cisplatin at doses of 0.75/75 mg/m2 and one patient at doses of 1.0/75 mg/m2. Grade 2 alopecia was observed in six patients. One patient receiving TPT/cisplatin at 0.75/75 mg/m2 experienced grade 2 stomatitis. Two patients treated at doses of 0.75/75 mg/m2 and two patients at doses of 1.0/75 mg/m2 had grade 1 diarrhea.

Table 2 Dose levels and hematologic toxicity (/course). Dose level (mg/m 2 ) TPT

0.75 1.00

No. of patients

Cisplatin

75 75

11 4

No. of patients requiring dosereductions

4 1

No. of courses

Neutrophils Grade

33 4

3

4

7

23 4

Platelets Grade 4 > 5 days

13 4

Nadir

Grade

Nadir

Mean

Median

3

4

Mean

Median

547.7 80.5

342 15

6 1

2 1

114.7 52.5

108 50

1006 Tumor responses Thirteen patients were evaluable for tumor response. Two patients were not evaluable for response due to early treatment discontinuation for toxicity. A total of three responses lasting 14, 12 and six weeks were observed in patients receiving TPT/cisplatin at doses of 0.75/75 mg/m2 and one response lasting four weeks was observed in a patient treated with TPT/cisplatin at doses of 1.0/75 mg/m2. The overall response rate was 30.7% (95% CI 9%-61%) and included the disappearance of a 4 x 5 cm primary lung tumor with 81% tumor shrinkage of a liver metastases lasting 12 weeks in a 69year-old patient who received TPT/cisplatin at doses of 0.75/75 mg/m2. Discussion TPT, a water-soluble analogue of camptothecin, exhibited a broad antitumor activity in a variety of human cancer models in preclinical studies [7, 8]. In phase I trials, repeated and continuous injection of single agent TPT showed that its DLT was myelosuppression [17]. When single agent TPT was given as a 30-minute infusion daily for five days every three weeks, the DLT was primarily neutropenia of brief duration and the recommended starting dose for future phase II trials in pretreated patients was 1.5 mg/m2 [15, 16, 18]. With this schedule, non-hematologic toxicity (including alopecia, skin rash, diarrhea and vomiting) occurred infrequently and was mild to moderate in severity and manageable. Unlike camptothecin, TPT did not induce hemorrhagic cystitis. Pharmacokinetic analysis showed that TPT plasma disposition followed a biexponential model with renal elimination accounting for 38.7% [15, 19]. A further phase I and pharmacokinetic analysis showed that systemic plasma clearance of total TPT was significantly reduced in patients with moderate renal impairment defined as a creatinine clearance ranging between 20-39 ml/min [20]. In this recent study, the recommended starting dose of single-agent TPT in patients with renal impairment was 0.75 mg/m2 daily for five days every three weeks and the authors suggested that extensively pretreated patients might require further dose reductions. Synergistic or additive effects with cisplatin and other alkylating agents were obtained in several preclinical cancer models, including non-small-cell lung carcinoma, and suggested that TPT-based combinations might improve the chemotherapy in patients [9-13, 21]. One of the most likely mechanisms for synergistic or additive effects might be related to the interaction between the cleavable complexes formed by topoisomerase I-inhibitors and the DNA repair mechanism induced by exposure to alkylating drugs [21, 22]. Conversely, alkylating agents might interact with poly-(ADP-ribose) polymerase which plays a major role in conferring resistance to topoisomerase I-inhibitors [23, 24]. Therefore, the com-

mon broad spectrum of activity, the positive interactions against cellular DNA in tumor cells, and the non-overlapping toxicities of cisplatin and TPT made the combination attractive for future clinical trials. This prompted us to initiate a phase I trial to determine the toxicological profile and the MTD of TPT given as 30-minute infusion daily for five days in combination with a fixeddose of 75 mg/m2 cisplatin in untreated patients with non-small-cell lung carcinomas. In our study, the first dose level of 0.75/75 mg/m2 TPT/cisplatin was associated with intolerable myelosuppression, and, therefore, the dose levels evaluated in this study cannot be recommended for subsequent phase II investigations. In patients who received reduced doses of 0.6/75 mg/m2 TPT/ cisplatin, severe myelosuppression remained a major toxicity, suggesting that further dose reduction of TPT may be necessary to reach recommendable doses for future phase II study. Mild and infrequent non-hematologic toxicities included nausea/vomiting, alopecia, and anemia and did not seem to increase in frequency and intensity as compared to the toxicities of TPT and cisplatin administered as single agents. Similar results were previously reported in a phase I trial conducted by the Cancer and Leukemia Group B (CALGB) in patients with advanced solid tumors [18]. The CALGB schedule combined fixed doses of 1.0 mg/m2 TPT daily for five days with escalated doses of cisplatin from a starting dose of 25 mg/m2 on day 1 every three weeks. In the CALGB study, neutropenia was also the DLT. The recommended doses of TPT/cisplatin with this schedule were 1.0/50 mg/m2 without fUgrastim or 1.0/75 mg/m2 with filgrastim support and were associated with a grade 3 ^ neutropenia in 83% (15 of 18 cycles) and 93% (13 of 14 cycles) of courses, respectively. Using those recommended doses, a subsequent phase II study was initiated by the same group in previously untreated patients with advanced small-cell lung carcinoma [25]. Among 12 patients treated with TPT/cisplatin, five lethal sepsis were observed. In our study, a similar attempt to reach the TPT/cisplatin dose level of 1.0/75 mg/m2 without filgrastim led to dose-limiting neutropenia in all of the patients and to one toxic death due to a severe sepsis. This suggests that the combination of 1.0/75 mg/m2 TPT/cisplatin, with and without filgrastim, may be impossible to manage in open phase II trials for patients previously treated with chemotherapy and /or with poor performance status who frequently develop infections (such as patients with non-small-cell lung carcinomas). The importance of the sequence dependency of TPT and cisplatin has been recently investigated by Rowinsky et al. in a phase I study [26]. In this study, TPT was administered as a 30-minute infusion daily for five days and cisplatin was given either before TPT on day 1 or after TPT on day 5. The authors' recommended doses for phase II studies were 50 mg/m2 cisplatin followed by 0.75 mg/m2 TPT. However, this study emphasized that those doses should be limited to minimally pretreated patients with a good performance status. The results showed that at doses of 0.75/75 mg/m2, with and with-

1007 out granulocyte colony-stimulating factor, the TPT/cisplatin combination resulted in dose-limiting neutropenia in all of the patients treated with the sequence of cisplatin before TPT while the sequence of cisplatin after TPT was better tolerated. Based on their pharmacokinetic study showing that the AUC of TPT following treatment with cisplatin was substantially higher on day 5 than on day 1, the authors suggested that, in patients receiving cisplatin prior to TPT, cisplatin-related subclinical tubular toxicity may reduce the renal clearance of TPT. The reason for the disparity in recommended doses between our study and those published by Millers [18] and Rowinsky [26] remains unclear. Based on the possible pharmacokinetic interaction between cisplatin and TPT, it is possible that the fixed dose of 75 mg/m2 cisplatin selected in our study may account, at least in part, for the toxicity of this regimen and, therefore, that lower doses of cisplatin may lead to a better toxicologic profile. However, when the study was initiated, animal studies suggested that TPT and cisplatin could be administered at doses close to their individual MTD and did not presume increased myelotoxicity. Although evaluation of activity was not the aim of this study, it should be pointed out that this TPT-cisplatin combination led to objective responses in our population of patients with previously untreated non-small-cell lung cancers. In conclusion, our results and those of previous phase I studies have shown that neutropenia is the DLT of the combination of daily TPT for five days with cisplatin on day 1. This study suggests that, for future phase II studies with this schedule in routine patient population, many of which have poor performance status and are pretreated, the recommended dose for TPT would range below 0.6 mg/m2. Recent pharmacokinetic analyses show that the sequence of drug administration is crucial for toxicity. Although the sequence of cisplatin before TPT has been selected based on some preclinical studies showing maximal synergistic effects with this sequence, the dose-limiting myelosuppression observed in this clinical trial and the recent understanding of the pharmacokinetic interaction between those drugs may encourage the investigation of the alternate sequence of cisplatin after TPT in phase II studies.

Acknowledgements This study was supported by SmithKline Beecham Pharmaceuticals and by the Cancer Therapy and Research Foundation of South Texas. We would like to acknowledge the following investigators who participated in this trial: Drs. S. Katler, T. J. O'Rourke, A. Thurman, and J. Wall. The authors thank Vera Love (Cancer Therapy and Research Center, San Antonio, TX), Peggy Durack and Alice Louise Goodwin (Institute for Drug Development, San Antonio, TX) for their excellent assistance in collecting the data and preparing this manuscript for publication.

References 1. Potmesil MP. Camptothecins: From bench research to hospital wards. Cancer Res 1994; 54: 1431-9. 2. Slichenmyer WJ, Rowinsky EK, Donehower RC et al. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 1993; 85: 271-91. 3. Chen AY, Liu LF. DNA topoisomerases: Essential enzymes and lethal targets. Ann Rev Pharmacol Toxicol 1994; 34: 1991-2218. 4. Hsiang Y-H, Lihou MG, Liu LF. Arrest of replication forks by dmg-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 1989; 49: 5077-82. 5. Ryan AJ, Squires S, Strutt HL et al. Camptothecin cytotoxicity in mammalian cells is associated with induction of persistent double strand breaks in replicating DNA. Nucl Acids Res 1991; 19: 3295300. 6. Pommier Y, Leteurtre F, Fesen MR et al. Cellular determinants of sensitivity and resistance to DNA topoisomerase I inhibitors. Cancer Invest 1994; 12: 530-42. 7. Von Hoff DD, Burris HA, Eckardt J et al. Preclinical and phase I trials of topoisomerase I inhibitors. Cancer Chemother Pharmacol 1994; 34 (Suppl): 41-5. 8. Bums HA, Hanauske A-R, Johnson RK et al. Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro. J Natl Cancer Inst 1992; 84: 1816— 20. 9. Chou T-C, Motzer RJ, Tong Yet al. Computerized quantification of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: A rational approach to clinical protocol design. J Natl Cancer Inst 1994; 86: 1517-24. 10. Drewinko B, Loo TL, Green C. Combination chemotherapy in vitro with cis-dichlorodiammineplatinum (II). Cancer Treat Rep 1976; 63: 1619-25. 11. Johnson RK, McCabe FL, Yu Y. Combination regimens with topotecan in animal tumor models. Ann Oncol 1992; 3: 85 (Abstr). 12. Kaufman SH, Peereboom D, Buclcwalter CA et al. Cytotoxic interactions between topotecan and diverse anticancer agents in human cancer cell lines. J Natl Cancer Inst 1996; 88: 734-^11. 13. Katz EJ, Vick JS, Kling KM et al. Effects of topoisomerase modulators on cisplatin cytotoxicity in human ovarian carcinoma. Eur J Cancer 1990; 26: 724-7. 14. Creemers GJ, Bolis G, Gore M et al. Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: Results of a large European phase II study. J Clin Oncol 1996; 14: 3056-61. 15. Rowinsky EK, Grochou LB, Hendricks CB et al. Phase I and pharmacokinetic study of topotecan: A novel topoisomerase I inhibitor. J Clin Oncol 1992; 10: 647-56. 16. Slichenmyer WJ, Rowinsky EK, Growchow LB et al. Camptothecin analogues: studies from The Johns Hopkins Oncology Center. Cancer Chemother Pharmacol 1994; 34 (Suppl): 53-7. 17. Lynch T. Topotecan today. J Clin Oncol 1996; 14: 3053-5. 18. Miller AA, Hargis JB, Lilenbaum RC et al. Phase I study of topotecan and cisplatin in patients with advanced solid tumors: A Cancer and Leukemia Group B study. J Clin Oncol 1994; 12: 2743-50. 19. Grochow LB, Rowinsky EK, Johnson R et al. Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer. Drug Metabol Dispos 1992, 20: 706-13. 20. O'Reilly S, Rowinsky EK, Slichenmyer W et al. Phase I and pharmacokinetic study of topotecan in patients with impaired renal function. J Clin Oncol 1996; 14: 3062-73. 21. Fulcuda M, Nishio K, Kanzawa F et al. Synergy between cisplatin and topoisomerase I inhibitors, NB-506 and SN38 in human small cell lung cancer cells. Cancer Res 1996; 56: 789-93. 22. Mattern MR, Mong S-M, Bartus HFet al. Relationship between the intracellular effects of camptothecin and the inhibition of DNA topoisomerase I in cultured L1210 cells. Cancer Res 1987; 47: 1793-8. 23. Burkle A, Chen G, Kupper JH et al. Increased poly(ADP-ribosy-

1008 l)ation in intact cells by cisplatin treatment. Carcinogenesis 1993; 14: 559-61. 24. Bramson J, Prevost J, Malapetsa A et al. Poly(ADP-ribose) polymerase can bind melphalan damaged DNA. Cancer Res 1993; 53: 5370-3. 25. Miller A, Lilenbaum R, Lynch T et al. Treatment-related fatal sepsis from topotecan/cisplatin and topotecan/paclitaxel. J Clin Oncol 1996; 14: 1964-5. 26. Rowinsky EK, Kaufmann SH, Baker SD et al. Sequences of topotecan and cisplatin: Phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 1996; 14: 3074-84.

Received 10 June 1997; accepted 20 August 1997. Correspondence to: E. Raymond, MD Institut Gustave-Roussy 39, me Camille Desmoulins 94805, VillejuifCedex France

Address for reprints: Dr. D. D.Von Hoff Institute for Drug Development Cancer Therapy and Research Center 14960 Omicron Drive San Antonio, TX 78240 USA