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Sequencing Topotecan and Etoposide Plus Cisplatin to Overcome Topoisomerase I and II Resistance

A Pharmacodynamically Based Phase I Trial

Section of Developmental Therapeutics, Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, and Cancer Institute of New Jersey, New Brunswick, New Jersey 08903

	ABSTRACT

Top ABSTRACT INTRODUCTION METHODS AND MATERIALS RESULTS DISCUSSION REFERENCES

 
Purpose: Resistance to topoisomerase (TOP) 1 and 2 inhibitors is a potentially important reason for treatment failure, and may be related, in part, to a down-regulation of the specific TOP target. Investigators in our laboratories previously noted such a down-regulation of the target, along with a reciprocal up-regulation of the alternate TOP. Therefore, sequencing TOP inhibitors may provide a means for overcoming resistance to the TOP I and II inhibitors. Furthermore, point mutations in TOP I, which confer resistance to TOP I inhibitors, were associated with collateral sensitivity to cisplatin.

Experimental Design: A dose escalating Phase I trial of topotecan (at doses of 0.75 to 1.0 mg/m²/day) on days 1 to 3 with etoposide (70–80 mg/m²/day) and cisplatin (20–25 mg/m²/day) on days 8 to 10. The timing of the drug sequence was based on the prior Phase I pharmacokinetic and pharmacodynamic studies of camptothecin and etoposide, and the level of the TOP targets in peripheral blood monocytes.

Results: Fifteen patients (7 males and 8 females) received 40 courses of therapy across three dose levels. The median age was 56 (range, 39–77), and the median performance status was 1 (range, 0–2). The diagnoses included: non-small cell lung cancer (7) , head and neck cancer (2) , cancer of unknown primary (2) , and 1 each of ovarian cancer, prostate cancer, gastric cancer, and renal cancer. Level 1 (topotecan 1.0 mg/m²/day; etoposide 80 mg/m²/day; and cisplatin 25 mg/m²/day) produced severe and prolonged febrile neutropenia in the first patient treated, and the subsequent patients were then entered onto a reduced dose level (cohort 2: topotecan 0.75 mg/m²/day; etoposide 70 mg/m²/day; and cisplatin 20 mg/m²/day). Three of 6 patients on cohort 2 experienced grade IV neutropenia >5 days, and a decision was then made to add filgrastim at 5 µg/kg rather than additionally reduce the dosages (cohort 3). Eight patients were then treated on cohort 3, and 1 of the 8 patients experienced a grade 4 neutropenia. Thus, cohort level three 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, whereas 5 showed continued progression of their disease.

Conclusions: These data show that sequencing TOP 1 and 2 inhibitors is feasible, and topotecan 0.75 mg/m²/day days 1–3; etoposide 70 mg/m²/day days 8–10; and cisplatin 20 mg/m²/day days 8–10 with filgrastim at 5 µg/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.

	INTRODUCTION

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TOP² 1 and 2 inhibitors are agents with considerable activity in cancer chemotherapy. The TOP 2 inhibitors are well established and widely used in a broad spectrum of cancers, and form the basis of many chemotherapy combinations. The TOP 1 inhibitors, topotecan and irinotecan, are a relatively newer group of anticancer agents, but already have a wide range of activity in hematological and solid tumors. Despite the wide spectrum of antitumor activity of the TOP 1 and TOP 2 inhibitors, many tumors develop resistance to these agents resulting in treatment failure. Preclinical studies indicate that resistance to camptothecins is often accompanied by up-regulation of TOP 2, with resultant hypersensitivity to TOP 2-targeting drugs (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) . In addition, animal models indicate that the sequential administration of TOP 1- and TOP 2-targeting drugs can result in additive or synergistic antitumor activity (11, 12, 13) . Furthermore, immunostaining of leukemic cells obtained from patients treated with continuous infusion topotecan demonstrated increases in TOP 2 protein levels (14) , and in a K562 leukemic cell model pretreatment with topotecan significantly enhanced the cytotoxic effects of subsequent etoposide/mitoxantrone (15) . Bonner 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 etoposide over 3 days. These studies suggest that resistance to TOP 1 inhibitors is attributable, in part, to a down-regulation of the TOP 1 target, and a reciprocal up-regulation of TOP 2. Conversely, treatment with TOP 2 inhibitors results in a down-regulation of TOP 2 and an up-regulation of TOP 1. These observations would argue for an alternation of the TOP 1 and TOP 2 inhibitors to enhance the effectiveness of both. On the basis of these concepts, Gupta et al. (18) tested the sequence of oral camptothecin followed by etoposide. This study also evaluated the levels of TOP 1 and TOP 2 in peripheral blood monocytes to correlate the levels of the target TOPs with the treatment of the respective inhibitor drug. This study demonstrated a rapid down-regulation of TOP 1, and an up-regulation of TOP 2 at 8–10 days after the oral camptothecin. These studies demonstrated this reciprocal relationship and also helped to define the timing of the sequences. In subsequent studies, Saleem et al. (19) additionally showed that point mutations in TOP 1 produced collateral sensitivity to cisplatin. Therefore, we felt that adding cisplatin to the alternation of TOP 1 and TOP 2 inhibitors might reduce the emergence of resistance to these agents. Furthermore, as cisplatin adds activity to both TOP 2 inhibitors such as etoposide as well as the TOP 1 inhibitors, we felt that adding cisplatin to the sequence might produce a highly active combination. For example, etoposide plus cisplatin is an active combination for several solid tumors such as small cell lung cancer and testicular cancer (20 , 21) . Topotecan is an established second-line agent for small cell lung cancer and other cancers (22) . Thus, the sequence of topotecan and etoposide plus cisplatin would seem a worthwhile combination for testing. Thus, we developed this as one of two noncontrolled, prospective, escalating Phase I studies of alternating TOP 1 and TOP 2 combinations (23) using the previously defined (18) schedule to define the optimal dose for this sequence.

	METHODS AND MATERIALS

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Patients.
To participate in this trial, patients must have had histological or cytological proof of advanced cancer for which no other effective therapy was available. Patients also were required to have: an ECOG performance status of 2, normal hematological parameters (WBC count 3500/µl, granulocyte count BORDER="0">1500/µl, and platelet count >100,000/µl), normal liver function tests (serum bilirubin 2 mg/dl and aspartate aminotransferase <2 times upper limit of laboratory normal), normal renal function [serum creatinine 1.5 mg/dl (133 µmol/liter) and creatinine clearance >60 ml/min]. Patients were excluded from trial participation for a history of HIV infection, any uncontrolled infection, or for any concurrent severe medical problems unrelated to the malignancy, which could significantly limit full compliance with the study, or expose the patient to excessive risk of toxicity or limit life expectancy. Patients with symptomatic brain metastases were also excluded from trial participation. Potential patients also could not have received an investigational agent within 30 days of study entry, and must have been at least 30 days from any prior chemotherapy (>45 days for prior nitrosoureas), immunotherapy, or radiotherapy before starting protocol therapy. Patients may not have received any prior topotecan or other camptothecin. Patients could not have had a history of sensitivity to Escherichia coli-derived products or a history of allergic reactions to compounds chemically related to topotecan. Women of childbearing age were required to practice active contraception to participate. Childbearing potential was defined as women who were not surgically sterilized or postmenopausal; i.e., documented absence of menses for >1 year before entry onto trial. All of the patients were informed of the investigational nature of the trial, were informed of the available alternative therapies, and signed an informed consent, which was approved by the Institutional Review Board.

Pretreatment Screening.
Within 14 days of trial entry, all of the patients were required to undergo a complete history and physical examination with performance status, an electrocardiogram, a 24-h urine creatinine clearance, serum chemistries (sodium, potassium, calcium, blood urea nitrogen, creatinine, magnesium, total protein, and albumin), serum liver function tests (alkaline phosphatase, aspartate aminotransferase, and total bilirubin), and a serum pregnancy test (for women of child-bearing age). Within 30 days of entry, patients were required to undergo tumor measurements or appropriate imaging studies (where assessable). Within 3 days of starting therapy, patients were required to have hematological studies (complete blood count, differential, and platelet count).

Study Parameters.
During the course of the study, patients had weekly toxicity assessment, vital signs, and CBC with differential and platelet count. Patients had blood chemistries before each cycle and on day 15 of each cycle. In addition to the above, patients had an interim history and physical examination, tumor measurements, and performance status assessment before each cycle.

Treatment Plan.
The treatment cycle was planned to be 21 days. All of the agents were obtained from commercial supplies and prepared according to standard methods for each 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. Cisplatin was to be infused over 60 min at a dose range of 20–25 mg/m² /day on days 8–10. Etoposide was to be infused over 60 min at a dose range of 60–80 mg/m² /day on days 8–10 after the completion of the cisplatin infusion. gCSF was to be administered s.c. to patients in dose cohort 3 at a dose of 5 µg/kg/day starting on day 11 and continuing until the neutrophil count recovers to >10,000/µl. After two cycles of treatment, patients were evaluated for response. Patients with evidence of progressive disease were taken off study and followed for survival. For the chemotherapy to be delivered on day 8, the absolute neutrophil count had to be >1,000/µl, and the platelet count had to be >100,000/µl.

Dose Modifications and Toxicity.
Patients were treated in dosing cohorts of 3 patients as illustrated in Table 1 . Dose 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 experienced DLT, then the next treatment group could be treated at the next highest dose level. In the event of 2 dose-limiting toxicities in the dosing cohort, subsequent patients were entered according to the de-escalation scheme in Table 1 .

Patients who experienced a DLT could be retreated at the previous dose level on full recovery of the toxicity. The maximum tolerated dose was defined as that dose cohort level that was one level less than that in which 2 of 6 patients experienced a DLT.

All of the patients who received one dose of protocol therapy were considered evaluable for toxicity. All of the adverse events, whether observed by the physician or the patient, were to be documented and recorded in the medical record. All of the toxicity and adverse events were to be graded by the National Cancer Institute CTC version 2.0.

An adverse event was defined as any new, undesirable medical experience or change of an existing condition that occurs during or after treatment, whether or not considered treatment related. A serious adverse event was defined as any untoward medical occurrence that suggests a significant hazard or side effect that: results in death, is life threatening (places the patient at immediate risk of death), requires or prolongs inpatient hospitalization, is disabling or incapacitating, or produces a congenital anomaly or birth defect. Each adverse event was to be graded according to the National Cancer Institute CTC and its relationship to the protocol treatments assessed.

Treatment Evaluation and Response Criteria.
For those patients with assessable disease, standard criteria for response were used. Complete response was defined as complete disappearance of all of the measurable disease, resolution of all of the signs and symptoms, and normalization of all of the disease-associated abnormal biochemical changes lasting a minimum of 4 weeks and during which no new lesions appeared. A partial response was defined as a >50% reduction in the sum of the products of the perpendicular diameters of all of the measurable lesions lasting a minimum of 4 weeks, and during which no new lesions appeared, and no existing lesions enlarged. Stable disease was defined as a <50% decrease, and a <25% increase in the sum of the products of the perpendicular diameters of all of the measurable lesions lasting >8 weeks, and during which no new lesions appeared. Progressive disease was defined as an increase of 25% in sum of the products of the perpendicular diameters of all of the measurable lesions.

Removal of Patients from Study.
Patients were removed from study in the event of drug-related life-threatening toxicity, or laboratory abnormality, withdrawal of patient consent, protocol violation, progressive disease, or if it were not in the best interest of the patient according to the judgment of the treating physician. All of the toxicities were monitored by the Cancer Institute of New Jersey Phase I group, and were reported according to the policies and procedures set by the Institutional Review Board and Food and Drug Administration.

	RESULTS

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Fifteen patients were entered onto the trial, and the characteristics of the patients are shown in Table 2 . The 7 males and 8 females were generally very functional with a median ECOG performance status of 1. Seven of the patients had non-small cell lung cancer. All of the patients had received prior therapy with chemotherapy, radiotherapy, or both. Only 1 patient received only prior radiotherapy. No patient received more than two prior chemotherapy regimens. A total of 40 cycles of therapy were administered across three dosing cohorts to the 15 patients with a median of 2 cycles and a range of 1–7 cycles per patient. The dosing cohorts achieved and the numbers of patients per dosing cohort are shown in Table 3 .

The entire toxicity experience for all of the courses is illustrated in Table 4 . Myeloid suppression in the form of leukopenia, thrombocytopenia, and anemia were the most common grade 3 and 4 toxicities. One instance of grade 4 confusion/delusion was observed during the second course in a patient with prostate cancer on dose cohort 3. A central nervous system workup was negative for metastases, and the patient was taken off study. The confusion continued to wax and wane for several days before clearing off study. Five instances of dyspnea (grade 3) were seen on study, predominantly in patients with lung cancer or smoking-related lung disease, and their association with the protocol therapy could not be fully linked or excluded. Three thromboembolic events (grade 3) were seen on study, but their relationship to protocol therapy could not be firmly established or excluded. Other grade 3 toxicities included: diarrhea (2) , fatigue (1) , weakness (1) , dysphagia (1) , constipation (1) , and line infection (1) .

	DISCUSSION

Top ABSTRACT INTRODUCTION METHODS AND MATERIALS RESULTS DISCUSSION REFERENCES

 
Topotecan is one of several camptothecin derivatives that target TOP 1 This class of agents has strong and broad-spectrum antitumor activity, and is now approved for use in several human cancers including small cell lung cancer, ovarian cancer, 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 to be helpful. One of the potential explanations rests with the expression of the target TOPs. Multiple investigators demonstrated that TOP 1 levels become down-regulated after treatment with TOP 1 inhibitors whereas TOP 2 levels increase (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 14 , 16, 17, 18) . This led to the concept of sequential application of TOP 1 and TOP 2 inhibitors. Ando et al. (20) sequenced irinotecan on days 1–3 with etoposide on days 4–6 in a Phase I trial. Whereas the authors saw some responses, severe myelosuppression occurred, and they concluded that this was an inappropriate schedule. Crump et al. (14) tested topotecan daily for days 1–5 and etoposide on days 6–8 in adult patients with myeloid leukemia. They observed some responses in chronic myelogenous leukemia blast crisis, but mucositis was the DLT. Interestingly, they observed a transient increase in TOP 2 levels in the peripheral blasts, but no correlation with clinical response was made. Tolcher et al. (21) tested the sequence of escalating doses of 72-h continuous infusion topotecan followed on day 5 by doxorubicin. They found the sequence feasible with myelosuppression and noted an increase in CD34+ cells in S phase 24 h after the topotecan. Seiden et al. (22) tested the sequence of doxorubicin followed 48 h later with 3 consecutive days of topotecan. They noted responses in their Phase I study and felt that the myelosuppression was manageable.

Licitra et al. (23) studied topotecan for 72 h followed by etoposide on days 8–10. They found some responses and occasional increased TOP 2 levels in tumor tissue, but also found severe myelosuppression, and questioned whether the sequence would be better than the single agents. Hammond et al. (24) tested the sequence of topotecan by 72-h continuous infusion followed by etoposide p.o. on days 7–9 in Phase II trials in non-small cell lung cancer. They observed 3 responses among the 19 patients entered onto trial, as well as a 33% 1-year survival, but felt that the responses were inadequate. They also postulated that earlier use of a TOP 2 inhibitor was appropriate. However, this level of response and 1-year survival for a nonplatinum-based regimen in non-small cell lung cancer seems quite interesting. Furthermore, based on our prior study by Gupta et al. (18) , we felt that additional study of the sequenced TOP 1 and TOP 2 inhibitors with the TOP 2 inhibitor given at 8–10 days would be worthwhile. In addition, we thus built on the study by Gupta et al. (18) and Saleem et al. (19) to develop the sequence of topotecan and etoposide plus cisplatin with the idea that such a sequence might prove useful in diseases such as small cell lung cancer or testicular cancer where either etoposide plus cisplatin or topotecan had some antitumor activities.

Fifteen patients were entered onto the current trial. The first patient onto this Phase I trial experienced significant DLT in the form of prolonged and severe febrile neutropenia. Accordingly, we accrued subsequent patients onto a reduced dose cohort as per protocol plan. Three of 6 patients in the reduced dose cohort experienced grade 4 neutropenia, and we then made a decision to add gCSF on day 11 as opposed to additional reducing dose. Whether adding gCSF on days 4–7, or more, might have additionally reduced myelosuppression is unclear, but we chose not to add it just before etoposide. The resulting dose cohort produced transient grade 4 neutropenia in 2 of 8 patients and otherwise acceptable levels of reversible nonmyeloid toxicities. Therefore, we felt that this then represented the dose for Phase II testing. These data show that the sequence of topotecan and etoposide plus cisplatin is feasible, and worthy of additional testing in a Phase II study. This sequence is planned as one arm of a randomized Phase II trial of alternating TOP 1 and TOP 2 inhibitors in small cell lung cancer by the ECOG.

	FOOTNOTES

 
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 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, and Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903.

² The abbreviations used are: TOP, topoisomerase; ECOG, Eastern Cooperative Oncology Group; gCSFm filgrastim; DLT, dose-limiting toxicity; CTC, common toxicity criteria.

Received 9/12/02; revised 2/13/03; accepted 2/14/03.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aisner, J. Articles by Rubin, E. H. Search for Related Content PubMed PubMed Citation Articles by Aisner, J. Articles by Rubin, E. H.