Sequencing Topotecan and Etoposide Plus Cisplatin to Overcome Topoisomerase I and II Resistance: a Pharmacodynamically Based Phase I Trial

2504 Vol. 9, 2504–2509, July 2003 Clinical Cancer Research

Sequencing Topotecan and Etoposide Plus Cisplatin to Overcome Topoisomerase I and II Resistance: A Pharmacodynamically Based Phase I Trial

Joseph Aisner,1 Rita Musanti, Stephanie Beers, day; and cisplatin 20 mg/m2/day). Three of 6 patients on Sharon Smith, Stephanie Locsin, and cohort 2 experienced grade IV neutropenia >5 days, and a ␮ Eric H. Rubin decision was then made to add filgrastim at 5 g/kg rather than additionally reduce the dosages (cohort 3). Eight pa- Section of Developmental Therapeutics, Division of Medical tients were then treated on cohort 3, and 1 of the 8 patients Oncology, Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, and experienced a grade 4 neutropenia. Thus, cohort level three Cancer Institute of New Jersey, New Brunswick, New Jersey 08903 was considered the recommended dose for Phase II studies. Twelve of the 15 patients had disease assessable for response to therapy. Seven achieved stable disease for >2 months, ABSTRACT whereas 5 showed continued progression of their disease. Purpose: Resistance to topoisomerase (TOP) 1 and 2 Conclusions: These data show that sequencing TOP 1 inhibitors is a potentially important reason for treatment and 2 inhibitors is feasible, and topotecan 0.75 mg/m2/day failure, and may be related, in part, to a down-regulation of days 1–3; etoposide 70 mg/m2/day days 8–10; and cisplatin the specific TOP target. Investigators in our laboratories 20 mg/m2/day days 8–10 with filgrastim at 5 ␮g/kg is an previously noted such a down-regulation of the target, along appropriate dose and schedule to test the concept of modu- with a reciprocal up-regulation of the alternate TOP. There- lating TOP levels by sequencing the administration of the fore, sequencing TOP inhibitors may provide a means for respective TOP inhibitors. overcoming resistance to the TOP I and II inhibitors. Fur- thermore, point mutations in TOP I, which confer resistance INTRODUCTION to TOP I inhibitors, were associated with collateral sensitiv- 2 TOP 1 and 2 inhibitors are agents with considerable ity to cisplatin. activity in cancer chemotherapy. The TOP 2 inhibitors are well Experimental Design: A dose escalating Phase I trial of established and widely used in a broad spectrum of cancers, and topotecan (at doses of 0.75 to 1.0 mg/m2 /day) on days 1 to 3 form the basis of many chemotherapy combinations. The TOP 1 with etoposide (70–80 mg/m2/day) and cisplatin (20–25 mg/ 2 inhibitors, topotecan and irinotecan, are a relatively newer group m /day) on days 8 to 10. The timing of the drug sequence of anticancer agents, but already have a wide range of activity in was based on the prior Phase I pharmacokinetic and phar- hematological and solid tumors. Despite the wide spectrum of macodynamic studies of camptothecin and etoposide, and antitumor activity of the TOP 1 and TOP 2 inhibitors, many the level of the TOP targets in peripheral blood monocytes. tumors develop resistance to these agents resulting in treatment Results: Fifteen patients (7 males and 8 females) re- failure. Preclinical studies indicate that resistance to camptoth- ceived 40 courses of therapy across three dose levels. The ecins is often accompanied by up-regulation of TOP 2, with median age was 56 (range, 39–77), and the median perform- resultant hypersensitivity to TOP 2-targeting drugs (1–10). In ance status was 1 (range, 0–2). The diagnoses included: addition, animal models indicate that the sequential administra- non-small cell lung cancer (7), head and neck cancer (2), tion of TOP 1- and TOP 2-targeting drugs can result in additive cancer of unknown primary (2), and 1 each of ovarian or synergistic antitumor activity (11–13). Furthermore, immu- cancer, prostate cancer, gastric cancer, and renal cancer. nostaining of leukemic cells obtained from patients treated with Level 1 (topotecan 1.0 mg/m2/day; etoposide 80 mg/m2/day; 2 continuous infusion topotecan demonstrated increases in TOP and cisplatin 25 mg/m /day) produced severe and prolonged 2␣ protein levels (14), and in a K562 leukemic cell model febrile neutropenia in the first patient treated, and the sub- pretreatment with topotecan significantly enhanced the cyto- sequent patients were then entered onto a reduced dose level 2 2 toxic effects of subsequent etoposide/mitoxantrone (15). Bonner (cohort 2: topotecan 0.75 mg/m /day; etoposide 70 mg/m / and Kozelsky (16) showed that there is a sequence dependence for TOP 1 and 2 inhibitors, and Eckardt et al. (17) demonstrated an up-regulation of TOP-2 after continuous i.v. infusion over 3 days of topotecan, and decreased after i.v. administration of Received 9/12/02; revised 2/13/03; accepted 2/14/03. The costs of publication of this article were defrayed in part by the etoposide over 3 days. These studies suggest that resistance to payment of page charges. This article must therefore be hereby marked TOP 1 inhibitors is attributable, in part, to a down-regulation of advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 2 The abbreviations used are: TOP, topoisomerase; ECOG, Eastern and Cancer Institute of New Jersey, 195 Little Albany Street, New Cooperative Oncology Group; gCSFm filgrastim; DLT, dose-limiting Brunswick, NJ 08903. toxicity; CTC, common toxicity criteria.

Table 1 Dose scheme No. of Topotecan dose Cisplatin dose Etoposide dose gCSF Cohort patients mg/m2/day mg/m2/day mg/m2/day 5 ␮g/kg/day Dose escalation scheme 1 3 1.0 25 80 0 2 3 0.75 20 70 0 3 3 0.75 20 70 Starting day 11 4 3 0.75 20 80 Starting day 11 5 3 1.0 20 80 Starting day 11 Dose de-escalation from prior dose level N-1 3 Ϫ0.25a Ϫ5a Ϫ10a Starting day 11 a Reduction.

the TOP 1 target, and a reciprocal up-regulation of TOP 2. problems unrelated to the malignancy, which could significantly Conversely, treatment with TOP 2 inhibitors results in a down- limit full compliance with the study, or expose the patient to regulation of TOP 2 and an up-regulation of TOP 1. These excessive risk of toxicity or limit life expectancy. Patients with observations would argue for an alternation of the TOP 1 and symptomatic brain metastases were also excluded from trial TOP 2 inhibitors to enhance the effectiveness of both. On the participation. Potential patients also could not have received an basis of these concepts, Gupta et al. (18) tested the sequence of investigational agent within 30 days of study entry, and must oral camptothecin followed by etoposide. This study also eval- have been at least 30 days from any prior chemotherapy (Ͼ45 uated the levels of TOP 1 and TOP 2 in peripheral blood days for prior nitrosoureas), immunotherapy, or radiotherapy monocytes to correlate the levels of the target TOPs with the before starting protocol therapy. Patients may not have received treatment of the respective inhibitor drug. This study demon- any prior topotecan or other camptothecin. Patients could not strated a rapid down-regulation of TOP 1, and an up-regulation have had a history of sensitivity to Escherichia coli-derived ofTOP2at8–10 days after the oral camptothecin. These products or a history of allergic reactions to compounds chem- studies demonstrated this reciprocal relationship and also helped ically related to topotecan. Women of childbearing age were to define the timing of the sequences. In subsequent studies, required to practice active contraception to participate. Child- Saleem et al. (19) additionally showed that point mutations in bearing potential was defined as women who were not surgi- TOP 1 produced collateral sensitivity to cisplatin. Therefore, we cally sterilized or postmenopausal; i.e., documented absence of felt that adding cisplatin to the alternation of TOP 1 and TOP 2 menses for Ͼ1 year before entry onto trial. All of the patients inhibitors might reduce the emergence of resistance to these were informed of the investigational nature of the trial, were agents. Furthermore, as cisplatin adds activity to both TOP 2 informed of the available alternative therapies, and signed an inhibitors such as etoposide as well as the TOP 1 inhibitors, we informed consent, which was approved by the Institutional felt that adding cisplatin to the sequence might produce a highly Review Board. active combination. For example, etoposide plus cisplatin is an Pretreatment Screening. Within 14 days of trial entry, active combination for several solid tumors such as small cell all of the patients were required to undergo a complete history lung cancer and testicular cancer (20, 21). Topotecan is an and physical examination with performance status, an electro- established second-line agent for small cell lung cancer and cardiogram, a 24-h urine creatinine clearance, serum chemistries other cancers (22). Thus, the sequence of topotecan and etopo- (sodium, potassium, calcium, blood urea nitrogen, creatinine, side plus cisplatin would seem a worthwhile combination for magnesium, total protein, and albumin), serum liver function testing. Thus, we developed this as one of two noncontrolled, tests (alkaline phosphatase, aspartate aminotransferase, and total prospective, escalating Phase I studies of alternating TOP 1 and bilirubin), and a serum pregnancy test (for women of child- TOP 2 combinations (23) using the previously defined (18) bearing age). Within 30 days of entry, patients were required to schedule to define the optimal dose for this sequence. undergo tumor measurements or appropriate imaging studies (where assessable). Within 3 days of starting therapy, patients METHODS AND MATERIALS were required to have hematological studies (complete blood Patients. To participate in this trial, patients must have count, differential, and platelet count). had histological or cytological proof of advanced cancer for Study Parameters. During the course of the study, pa- which no other effective therapy was available. Patients also tients had weekly toxicity assessment, vital signs, and CBC with were required to have: an ECOG performance status of Յ2, differential and platelet count. Patients had blood chemistries normal hematological parameters (WBC count Ն3500/␮l, gran- before each cycle and on day 15 of each cycle. In addition to the ulocyte count Ն1500/␮l, and platelet count Ͼ100,000/␮l), nor- above, patients had an interim history and physical examination, mal liver function tests (serum bilirubin Յ2 mg/dl and aspartate tumor measurements, and performance status assessment before aminotransferase Ͻ2 times upper limit of laboratory normal), each cycle. normal renal function [serum creatinine Յ1.5 mg/dl (133 ␮mol/ Treatment Plan. The treatment cycle was planned to be liter) and creatinine clearance Ͼ60 ml/min]. Patients were ex- 21 days. All of the agents were obtained from commercial cluded from trial participation for a history of HIV infection, supplies and prepared according to standard methods for each any uncontrolled infection, or for any concurrent severe medical agent. Topotecan was to be administered as a 30-min infusion

over a dose range of 0.50 to 1.0 mg/m2/day on days 1–3. Table 2 Patient characteristics Cisplatin was to be infused over 60 min at a dose range of Male/female 7/8 2 20–25 mg/m /day on days 8–10. Etoposide was to be infused Age median (range) 56 (39–77) over 60 min at a dose range of 60–80 mg/m2/day on days 8–10 Median performance status (range) 1 (0–2) after the completion of the cisplatin infusion. gCSF was to be Diagnoses administered s.c. to patients in dose cohort 3 at a dose of 5 Non-small cell lung cancer 7 Head and neck cancer 2 ␮g/kg/day starting on day 11 and continuing until the neutrophil Primary of unknown origin 2 count recovers to Ͼ10,000/␮l. After two cycles of treatment, Ovarian cancer 1 patients were evaluated for response. Patients with evidence of Prostate cancer 1 progressive disease were taken off study and followed for sur- Gastric cancer 1 Renal cancer 1 vival. For the chemotherapy to be delivered on day 8, the Prior therapies absolute neutrophil count had to be Ͼ1,000/␮l, and the platelet Radiotherapy 1 count had to be Ͼ100,000/␮l. Radiotherapy and chemotherapy 6 Dose Modifications and Toxicity. Patients were treated Chemotherapy 8 in dosing cohorts of 3 patients as illustrated in Table 1. Dose Median # prior chemotherapy cycles (range) 1 (0–2) Median # PET cycles given (range) 2 (1–7) escalations in subsequent cohorts were considered only after all 3 of the patients in the prior group had been observed for a full cycle (21 days) without any DLT. If 1 of 3 patients at a given dose level experienced a DLT, 3 additional patients were to be treated at that same dose. If no more than 1 of the 6 patients disease-associated abnormal biochemical changes lasting a min- experienced DLT, then the next treatment group could be treated imum of 4 weeks and during which no new lesions appeared. A Ͼ at the next highest dose level. In the event of 2 dose-limiting partial response was defined as a 50% reduction in the sum of toxicities in the dosing cohort, subsequent patients were entered the products of the perpendicular diameters of all of the mea- according to the de-escalation scheme in Table 1. surable lesions lasting a minimum of 4 weeks, and during which DLT was defined as any of the following occurring on the no new lesions appeared, and no existing lesions enlarged. Ͻ Ͻ first cycle of treatment: (a) grade 4 neutropenia (polymorpho- Stable disease was defined as a 50% decrease, and a 25% nuclear Ͻ500/␮l) or thrombocytopenia (platelet count Ͻ25,000/ increase in the sum of the products of the perpendicular diam- Ͼ ␮l) for Ͼ5 days; (b) irreversible grade 2 or any grade 3–5 eters of all of the measurable lesions lasting 8 weeks, and nonhematological toxicity (CTC criteria); (c) dose held on day during which no new lesions appeared. Progressive disease was Ն 8 because of absolute neutrophil count Ͻ1,000/␮l or platelet defined as an increase of 25% in sum of the products of the count Ͻ90,000/␮l; or (d) greater than a 2-week delay before perpendicular diameters of all of the measurable lesions. cycle 2. Removal of Patients from Study. Patients were re- Patients who experienced a DLT could be retreated at the moved from study in the event of drug-related life-threatening previous dose level on full recovery of the toxicity. The maxi- toxicity, or laboratory abnormality, withdrawal of patient con- mum tolerated dose was defined as that dose cohort level that sent, protocol violation, progressive disease, or if it were not in was one level less than that in which 2 of 6 patients experienced the best interest of the patient according to the judgment of the a DLT. treating physician. All of the toxicities were monitored by the All of the patients who received one dose of protocol Cancer Institute of New Jersey Phase I group, and were reported therapy were considered evaluable for toxicity. All of the ad- according to the policies and procedures set by the Institutional verse events, whether observed by the physician or the patient, Review Board and Food and Drug Administration. were to be documented and recorded in the medical record. All of the toxicity and adverse events were to be graded by the RESULTS National Cancer Institute CTC version 2.0. Fifteen patients were entered onto the trial, and the char- An adverse event was defined as any new, undesirable acteristics of the patients are shown in Table 2. The 7 males and medical experience or change of an existing condition that 8 females were generally very functional with a median ECOG occurs during or after treatment, whether or not considered performance status of 1. Seven of the patients had non-small cell treatment related. A serious adverse event was defined as any lung cancer. All of the patients had received prior therapy with untoward medical occurrence that suggests a significant hazard chemotherapy, radiotherapy, or both. Only 1 patient received or side effect that: results in death, is life threatening (places the only prior radiotherapy. No patient received more than two prior patient at immediate risk of death), requires or prolongs inpa- chemotherapy regimens. A total of 40 cycles of therapy were tient hospitalization, is disabling or incapacitating, or produces administered across three dosing cohorts to the 15 patients with a congenital anomaly or birth defect. Each adverse event was to a median of 2 cycles and a range of 1–7 cycles per patient. The be graded according to the National Cancer Institute CTC and dosing cohorts achieved and the numbers of patients per dosing its relationship to the protocol treatments assessed. cohort are shown in Table 3. Treatment Evaluation and Response Criteria. For The patient who entered the first dose cohort (topotecan 1.0 those patients with assessable disease, standard criteria for re- mg/m2/day; cisplatin 25 mg/m2/day; etoposide 80 mg/m2/day; sponse were used. Complete response was defined as complete and no gCSF) experienced a grade 4 course 1 DLT in the form disappearance of all of the measurable disease, resolution of all of prolonged severe neutropenia with fever. In addition, he of the signs and symptoms, and normalization of all of the experienced grade 2 dysphagia and grade 2 fatigue. Thus, the

Table 3 Dosing cohort levels achieved Dose No. of mg/m2 mg/m2 mg/m2 gCSF Number cohort patients topotecan etoposide cisplatin given of DLTs Type of DLT 1 1 1.0 80 25 (Ϫ) 1 Febrile n-penia Ͼ5 days 2 6 0.75 70 20 (Ϫ) 3 n-penia Ͼ5 days 3 8 0.75 70 20 (ϩ) 1 n-penia

Table 4 Toxicities their relationship to protocol therapy could not be firmly estab- Toxicity type Grade 2 Grade 3 Grade 4 lished or excluded. Other grade 3 toxicities included: diarrhea (2), fatigue (1), weakness (1), dysphagia (1), constipation (1), Neutropenia (febrile) 1 3a 8a(1) Thrombocytopenia 0 3 1 and line infection (1). Anemia 1 6 1 Response. Because this was a Phase I trial, there was no Dyspnea 4 5 0 entry requirement for assessable disease. Three patients came Fatigue 5 1 0 off study before their disease could be reassessed or did not have Pain 4 0 0 assessable disease. Among those patients whose disease was Depression 3 0 0 Diarrhea 1 2 0 assessable for response, there were no complete or partial re- Anxiety 2 0 0 sponses seen. However, 6 patients achieved stable disease; 3 Anorexia 2 0 0 with non-small cell lung cancer, and 1 each in unknown pri- DVT/PE 0 3 0 mary, prostate, and renal cancers. Six patients experienced pro- Edema 2 0 0 Confusion 1 0 1 gressive disease while on study: 3 with non-small cell lung Weakness 0 1 0 cancer, 2 with head and neck cancer, and 1 with unknown Dysphagia 0 1 0 primary. Hematuria 1 0 0 Hyperglycemia 1 0 0 Constipation 0 1 0 DISCUSSION Elevated LFT’s100 Topotecan is one of several camptothecin derivatives that Line infection 0 1 0 target TOP 1 This class of agents has strong and broad-spectrum Oral/vaginal thrush 2 0 0 antitumor activity, and is now approved for use in several a Ͼ ϭ ϭ ϭ Neutropenia 5 days DLT (n 4); febrile neutropenia human cancers including small cell lung cancer, ovarian cancer, DLT (n ϭ 1). and others. The induction of DNA damage by TOP 1 and TOP 2 inhibition is thus an important approach to the treatment of cancer, but their concurrent use in combination has not proven CINJ Phase I group decided to enter the second patient into a to be helpful. One of the potential explanations rests with the reduced dosing cohort as shown in Table 1. (topotecan 0.75 expression of the target TOPs. Multiple investigators demon- mg/m2/day; cisplatin 20 mg/m2/day; etoposide 70 mg/m2/day; strated that TOP 1 levels become down-regulated after treatment and no gCSF). Six patients were entered onto this dose cohort, with TOP 1 inhibitors whereas TOP 2 levels increase (1–10, 14, and 3 of the 6 experienced course 1, grade 4 neutropenia for Ͼ5 16–18). This led to the concept of sequential application of TOP days. This met the criteria of DLT, and a discussion by the CINJ 1 and TOP 2 inhibitors. Ando et al. (20) sequenced irinotecan on Phase I group considered either additional dose reduction or the days 1–3 with etoposide on days 4–6 in a Phase I trial. Whereas addition of gCSF, and decided to add gCSF as the third dose the authors saw some responses, severe myelosuppression oc- cohort (Table 3). Eight patients were entered onto dose cohort 3, curred, and they concluded that this was an inappropriate sched- and 1 course 1, grade 4 neutropenia (DLT) was observed. On the ule. Crump et al. (14) tested topotecan daily for days 1–5 and basis of these data, we felt that dose cohort 2 was the maximal etoposide on days 6–8 in adult patients with myeloid leukemia. tolerated dose, and dose cohort 3, i.e., with gCSF, represented They observed some responses in chronic myelogenous leuke- the recommended dose for Phase II study. mia blast crisis, but mucositis was the DLT. Interestingly, they The entire toxicity experience for all of the courses is observed a transient increase in TOP 2 levels in the peripheral illustrated in Table 4. Myeloid suppression in the form of blasts, but no correlation with clinical response was made. leukopenia, thrombocytopenia, and anemia were the most com- Tolcher et al. (21) tested the sequence of escalating doses of mon grade 3 and 4 toxicities. One instance of grade 4 confusion/ 72-h continuous infusion topotecan followed on day 5 by doxo- delusion was observed during the second course in a patient rubicin. They found the sequence feasible with myelosuppres- with prostate cancer on dose cohort 3. A central nervous system sion and noted an increase in CD34ϩ cells in S phase 24 h after workup was negative for metastases, and the patient was taken the topotecan. Seiden et al. (22) tested the sequence of doxoru- off study. The confusion continued to wax and wane for several bicin followed 48 h later with 3 consecutive days of topotecan. days before clearing off study. Five instances of dyspnea (grade They noted responses in their Phase I study and felt that the 3) were seen on study, predominantly in patients with lung myelosuppression was manageable. cancer or smoking-related lung disease, and their association Licitra et al. (23) studied topotecan for 72 h followed by with the protocol therapy could not be fully linked or excluded. etoposide on days 8–10. They found some responses and occa- Three thromboembolic events (grade 3) were seen on study, but sional increased TOP 2 levels in tumor tissue, but also found

severe myelosuppression, and questioned whether the sequence 7. Rubin, E., Pantazis, P., Bharti, A., Toppmeyer, D., Giovanella, B., would be better than the single agents. Hammond et al. (24) and Kufe, D. Identification of a mutant human topoisomerase with intact tested the sequence of topotecan by 72-h continuous infusion catalytic activity and resistance to 9-nitro-camptothecin. J. Biol. Chem., 269: 2433–2439, 1994. followed by etoposide p.o. on days 7–9 in Phase II trials in 8. Tan, K. B., Mattern, M. R., Eng, W., McCabe, F. L., and Johnson, non-small cell lung cancer. They observed 3 responses among R. K. Non-productive rearrangement of DNA topoisomerase I and II the 19 patients entered onto trial, as well as a 33% 1-year genes: correlation with resistance to topoisomerase I inhibitors. J. Natl. survival, but felt that the responses were inadequate. They also Cancer Inst., 81: 1732–1735, 1989. postulated that earlier use of a TOP 2 inhibitor was appropriate. 9. Lefevre, D., Riou, J. F., Ahomadegbe, J. C., Zhou, D. Y., Bernard, J., However, this level of response and 1-year survival for a non- and Riou, G. Study of molecular markers of resistance to m-AMSA in platinum-based regimen in non-small cell lung cancer seems a human breast cancer cell line. Decrease of topoisomerase II and quite interesting. Furthermore, based on our prior study by increase of both topoisomerase I and acid glutathione S-transferase. Biochem. Pharmacol., 41: 1967–1979, 1991. Gupta et al. (18), we felt that additional study of the sequenced 10. Riou, J., Grondard, L., Petitgenet, O., Abitbol, M., and Lavelle, F. TOP 1 and TOP 2 inhibitors with the TOP 2 inhibitor given at Altered topoisomerase I activity and recombinant activating gene ex- 8–10 days would be worthwhile. In addition, we thus built on pression in a human leukemia cell line resistant to doxorubicin. Bio- the study by Gupta et al. (18) and Saleem et al. (19) to develop chem. Pharmacol., 46: 851–861, 1993. the sequence of topotecan and etoposide plus cisplatin with the 11. Matsumoto, N., Nakano, S., Esaki, T., Tatsumoto, T., Fujishima, H., idea that such a sequence might prove useful in diseases such as Baba, E., Nakamura, M., and Niho, Y. Sequence-dependent modulation small cell lung cancer or testicular cancer where either etoposide of anticancer drug activities by 7-ethyl-10-hydroxycamptothecin in an plus cisplatin or topotecan had some antitumor activities. HST-1 human squamous carcinoma cell line. Anticancer Res., 15: 405–409, 1995. Fifteen patients were entered onto the current trial. The first 12. Eder, J. P., Chan, V., Wong, J., Wong, Y. W., Ara, G., Northey, D., patient onto this Phase I trial experienced significant DLT in the Rizvi, N., and Teicher, B. A. Sequence effect of irinotecan (CPT-11) form of prolonged and severe febrile neutropenia. Accordingly, and topoisomerase II inhibitors in vivo. Cancer Chemother. Pharmacol., we accrued subsequent patients onto a reduced dose cohort as 42: 327–335, 1998. per protocol plan. Three of 6 patients in the reduced dose cohort 13. Whitacre, C. M., Zborowska, E., Gordon, N. H., Mackay, W., and experienced grade 4 neutropenia, and we then made a decision Berger, N. A. Topotecan increases topoisomerase IIa levels and sensi- to add gCSF on day 11 as opposed to additional reducing dose. tivity to treatment with etoposide in a schedule-dependent process. Cancer Res., 57: 1425–1428, 1997. Whether adding gCSF on days 4–7, or more, might have additionally reduced myelosuppression is unclear, but we chose not 14. Crump, M., Lipton, J., Hedley, D., Sutton, D., Shepherd, F., Min- den, M., Stewart, K., Beare, S., and Eisenhauer, E. Phase I trial of to add it just before etoposide. The resulting dose cohort pro- sequential topotecan followed by etoposide in adults with myeloid duced transient grade 4 neutropenia in 2 of 8 patients and leukemia: a National Cancer Institute of Canada Clinical Trials Group otherwise acceptable levels of reversible nonmyeloid toxicities. Study. Leukemia (Baltimore), 13: 343–347, 1999. Therefore, we felt that this then represented the dose for Phase 15. Chen, S., Gomez, S. P., McCarley, D., and Mainwaring, M. G. II testing. These data show that the sequence of topotecan and Topotecan-induced topoisomerase II ␣ expression increases the sen- etoposide plus cisplatin is feasible, and worthy of additional sitivity of the CML cell line K562 to subsequent etoposide plus mitoxantrone treatment. Cancer Chemother. Pharmacol., 49: 347– testing in a Phase II study. This sequence is planned as one arm 355, 2002. of a randomized Phase II trial of alternating TOP 1 and TOP 2 16. Bonner, J. A., and Kozelsky, T. F. The significance of the sequence inhibitors in small cell lung cancer by the ECOG. of administration topotecan and etoposide. Cancer Chemother. Pharma- col., 39: 109–112, 1996. 17. Eckardt, J. R., Burris, H. A., Von Hoff, D. D., Rodriguez, G. I., REFERENCES Fields, S. M., Rothenberg, M. L., Moore, T. D., Hodges, S., Weiss, 1. Gupta, R. S., Gupta, R., Eng, B., Lock, R. B., Ross, W. E., Hertzberg, G. R., Cobb, P., Rinaldi, D., Kuhn, J. G., Ford, J., and Ganapathi, R. R. P., Caranfa, M. J., and Johnson, R. K. Camptothecin-resistant mu- Measurement of tumor topoisomerase I and II levels during the sequen- tants of Chinese hamster ovary cells containing a resistant form of tial administration of topotecan and etoposide. Proc. Am. Soc. Clin. topoisomerase I. Cancer Res., 48: 6404–6410, 1988. Oncol., 13: 141, 1994. 2. Eng, W. K., McCabe, F. L., Tan, K. B., Mattern, M. R., Hofman, 18. Gupta, E., Toppmeyer, D., Zamek, R., Much, J., Ibrahim, N., G. A., Woessner, R. D., Hertzberg, R. P., and Johnson, R. K. Develop- Goodin, S., Kane, M., Aisner, J., Li, X. G., Haluska, P., Jr., Medina, ment of a stable camptothecin-resistant subline of P388 leukemia with M., Cornfield, A., Vyas, V., Natelson, E., Giovanella, B., Saleem, A., reduced topoisomerase I content. Mol. Pharmacol., 38: 471–480, 1990. and Rubin, E. Clinical evaluation of sequential topoisomerase tar- 3. Sugimoto, Y., Tsukahara, S., Oh-hara, T., Liu, L. F., and Tsuruo, T. geting in the treatment of advanced malignancy. Cancer Ther., 1: Elevated expression of DNA topoisomerase II in camptothecin-resistant 292–301, 1998. human tumor cell lines. Cancer Res., 50: 7962–7965, 1990. 19. Saleem, A., Ibrahim, N., Patel, M., Li, X. G., Gupta, E., Mendoza, 4. Woessner, R. D., Eng, W., Hoffman, G. A., Rieman, D. J., McCabe, J., Pantazis, P., and Rubin, E. H. Mechanisms of resistance in human F. L., Hertzberg, R. P., Mattern, M. R., Tan, K. B., and Johnson, R. K. cell lines exposed to sequential topoisomerase poisoning. Cancer Res., Camptothecin hyper-resistant P388 cells; Drug dependent reduction in 57: 5100–5106, 1997. topoisomerase I content. Oncol. Res., 4: 481–488, 1992. 20. Ando, M., Eguchi, K., Shinkai, T., Tamura, T., Ohe, Y., Yamamoto, 5. Chang, J., Dethlefsen, L. A., Barley, L. R., Zhou, B., and Cheng, N., Kurata, T., Kasai, T., Ohmatsu, H., Kubota, K., Sekine, I., Hojo, N., Y. C. Characterization of camptothecin-resistant Chinese Hamster lung Matsumoto, T., Kodama, T., Kakinuma, R., Nishiwaki, Y., and Saijo, cells. Biochem. Pharmacol., 43: 2443–2452, 1992. N. Phase I study of sequentially administered topoisomerase I in- 6. Tanizawa, A., and Pommier, Y. Topoisomerase I alternation in a hibitor (irinotecan) and topoisomerase II inhibitor (etoposide) for camptothecin-resistant cell line derived from Chinese Hamster DC3F metastatic non-small-cell lung cancer. Br. J. Cancer, 76: 1494– cells in culture. Cancer Res., 52: 1848–1854, 1992. 1499, 1997.

21. Tolcher, A. W., O’Shaughnessy, J. A., Weiss, R. B., Zujewski, targeting in combination with cisplatin in the treatment of patients with J., Myhand, R. C., Schneider, E., Hakim, F., Gress, R., Goldspiel, B., advanced solid tumors. Clin. Cancer Res., in press. Noone, M. H., Brewster, L. R. Gossard, M. R., and Cowan, K. H. 24. Hammond, L. A., Eckardt, J. R., Ganapathi, R., Burris, H. A., Phase I study of topotecan followed sequentially by doxorubicin in Rodriguez, G. A., Eckhardt, S. G., Rothenberg, M. L., Weiss, G. R., patients with advanced malignancies. Clin. Cancer Res., 3: 755–760, Kuhn, J. G., Hodges, S., Von Hoff, D. D., and Rowinsky, E. K. A phase 1997. I and translational study of sequential administration of the topoisomer- 22. Seiden, M. V., Ng, S. W., Supko, J. G., Ryan, D. P., Clark, J. W., ase I and II inhibitors topotecan and etoposide. Clin. Cancer Res., 4: Lynch, T., Huang, K. C., Kwiatkowski, D., Skarin, A., and Eder, J. P., 1459–1467, 1998. Jr. A phase I clinical trial of sequentially administered doxorubicin and 25. Dowlati, A., Levitan, N. H., Hoppel, C. L., Gosky, D. M., topotecan in refractory solid tumors. Clin. Cancer Res., 8: 691–697, Remick, S. C., Ingalls, S. T., Berger, S. J., and Berger, N. A. Phase 2002. II and pharmacokinetic / pharmacodynamic trial of sequential topoi- 23. Licitra, E. J., Vyas, V., Nelson, K., Musanti, R., Beers, S., Thomas, somerase I and II inhibition with topotecan and etoposide in ad- C., Saleem, A., Poplin, E., Lin, Y., Schaaf, L. J., Toppmeyer, D., and vanced non-small-cell lung cancer. Cancer Chemother. Pharmacol., Rubin, E. H. Phase I clinical evaluation of sequential topoisomerase 47: 141–1448, 2001.

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Joseph Aisner, Rita Musanti, Stephanie Beers, et al.

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