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Originally published as JCO Early Release 10.1200/JCO.2002.09.030 on July 9 2002 © 2002 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of E7070, a Novel Chloroindolyl Sulfonamide Cell-Cycle Inhibitor, Administered as a One-Hour Infusion Every Three Weeks in Patients With Advanced CancerByFrom the Institut Gustave-Roussy, Villejuif, France; Netherlands Cancer Institute and NDDO Oncology, Amsterdam, the Netherlands; and Eisai Limited, London, United Kingdom. Address reprint requests to Eric Raymond, MD, PhD, Department of Medicine, Institut Gustave Roussy, 39 Rue Camille Desmoulins 94805 Villejuif, France; email: raymond{at}igr.fr
PURPOSE: The objectives were to determine the maximum-tolerated dose, the recommended dose, the dose-limiting toxicity, the pharmacokinetics, and the activity of E7070, a novel cell-cycle inhibitor. PATIENTS AND METHODS: E7070 was given as a 1-hour intravenous infusion every 3 weeks in two groups of patients with advanced solid tumors who met prespecified eligibility criteria (group A) or who met the same eligibility criteria but in addition were less heavily pretreated and had more favorable liver functions (group B).
RESULTS: Forty patients (31 patients in group A and nine patients in group B) were entered. Dose escalation proceeded through eight levels (range, 50 to 1,000 mg/m2). In group A, neutropenia and thrombocytopenia were dose-limiting toxicities occurring during the first cycle in two of seven patients treated at the doses of 700 mg/m2 and two of four patients treated at 800 mg/m2. Identical dose-limiting toxicities were observed in zero of six and two of three patients from group B at doses of 800 and 1,000 mg/m2, respectively. Other toxicities included acne-like skin eruption, mucositis, conjunctivitis, nausea, fatigue, and alopecia. At doses greater than 400 mg/m2, the area under the concentration-time curve increased disproportionately to the administered dose. Tumor stabilization lasting CONCLUSION: The recommended doses of E7070 in this schedule were 700 mg/m2 (group A) and 800 mg/m2 in patients who were less heavily pretreated (group B) with a moderate tumor burden. Prolonged disease stabilization observed in this study might warrant further investigation of E7070 in selected tumor types.
DEREGULATED CELL proliferation following the loss of cell-cycle control is one of the hallmarks of cancer.1,2 The cyclin-dependent kinases (CDKs) are catalytic subunits that act in combination with individual cyclins to regulate the orderly progression of cells through mitosis. The recent identification and purification of these enzymes makes them potential targets for new anticancer drugs, and several CDK inhibitors are currently under preclinical and clinical evaluation.3-7 E7070 (Fig 1) is a novel chloroindolyl sulfonamide8 that induces both G1-S and G2-M arrest in HCT-116 human colon cancer cells, possibly through downregulation of cyclin H.9,10 At higher concentrations, E7070 upregulates p53 and p21 with subsequent apoptotic cell death.10-12 In the National Cancer Institute (NCI) COMPARE screening program, E7070 displayed low correlation coefficients when compared with other anticancer drugs, suggesting a unique mechanism of action.4,10-13 In addition to the HCT-116 cell line, cytotoxic effects have been observed in a wide variety of other human cancer cell lines after treatment with E7070 at concentrations ranging between 0.05 and 100 µg/mL. Further studies have also demonstrated antitumor effects of E7070 in athymic mice bearing ectotopic and orthotopic human colon cancer and non–small-cell lung cancer xenografts, with cures being reported in some animals.10-12 In vivo, E7070 shows similarities with chloroquinoxaline sulfonamide, a compound developed by the NCI that was shown to exhibit a hazardous toxicity profile characterized by dose-limiting hypoglycemia and cardiac tachyarrhythmias that prevented its further clinical development.14-17 Although the mechanism of action of chloroquinoxaline sulfonamide and E7070 are thought to be similar,18 E7070 displayed antiproliferative effects that were approximately 10 times more potent than that of chloroquinoxaline sulfonamide in human colon and non–small-cell lung cancer models.
Toxicology studies of E7070 in mice, rats, and dogs have shown that E7070 can inhibit carbonic anhydrase and thus may alter electrolyte homeostasis and intraocular pressure. Sporadic fluctuations of blood glucose and QT interval were also reported at the maximum-tolerated dose (MTD) of E7070 in rats and beagle dogs, respectively. Although this toxicity profile was consistent with that of chloroquinoxaline sulfonamide, the adverse effects of E7070 were observed only at higher dose levels and were rapidly reversible. Based on its unique mechanism of action and its broad spectrum of activity, E7070 was selected for phase I clinical trials using a variety of schedules. Apart from our study, three other schedules were explored, investigating a daily-for-5-days infusion once every 3 weeks, a weekly injection for 4 weeks, and a protracted continuous infusion. As part of these studies, additional toxicity assessments were directed toward the early detection of the established adverse effects of chloroquinoxaline sulfonamide and E7070 as reported from animal toxicity studies. The objectives of this study were (1) to determine the MTD and recommended dose of E7070 for further study when given as a 1-hour infusion repeated every 3 weeks, (2) to describe the principal toxicities of that schedule, (3) to assess its pharmacokinetic profile, and (4) to document any antitumor activity. In order to avoid underestimating the recommended safe dose of E7070 for further study, dose escalation was performed sequentially in two groups of patients: first in a cohort of patients (group A) who met classical criteria of phase I studies, and then further escalation was performed in a subsequent, less heavily pretreated cohort with a limited tumor burden (group B).
Patient Selection Patients entered onto study group A met the following criteria: histologically or cytologically confirmed diagnosis of solid tumor refractory to standard therapy or no standard therapy available; age  18 years; life expectancy of 3 months; World Health Organization (WHO) performance status  2; no chemotherapy, hormonal therapy, immunotherapy, or radiotherapy within 4 weeks before treatment with E7070 (6 weeks for previous treatment with nitrosoureas or mitomycin or for extensive radiotherapy); adequate hepatic function, defined as serum bilirubin less than 25 µmol/L (< 1.5 mg/dL), transaminase levels 2.5 times the upper limit of normal (ULN) ( five times ULN in case of liver metastases); adequate bone marrow function, including an absolute neutrophil count 1,500/µL, platelet count 100 000/µL, and hemoglobin level 9.0 g/dL; adequate renal function, with serum creatinine 120 µmol/L (1.4 mg/dL) and/or creatinine clearance (Cockroft formula) 60 mL/min; no history of alcoholism, drug addiction, or psychotic disorders; signed informed consent according to institutional and national guidelines; no medical condition which, in the opinion of the investigator, was incompatible with the protocol; and no uncontrolled systemic infection. Patients were excluded if they were pregnant or breast-feeding (men and women of childbearing potential were required to use a reliable method of contraception), had symptomatic brain metastases or leptomeningeal tumor involvement, were suffering from any disorder of intraocular pressure, or were receiving any of the following: concomitant antitumor therapy (except localized palliative radiotherapy), sulfonylureas for diabetes, or cardiac antiarrhythmic drugs. Patients were not required to have assessable or measurable disease.
In addition to meeting these criteria, patients allocated to group B must have had hepatic transaminase levels
Pretreatment and Follow-Up Examinations
In order to be assessable for response, patients must have had measurable disease as defined by WHO criteria and must have completed two courses of E7070 before reassessment. Tumor measurements were obtained at baseline and after every second course of E7070 thereafter. Responses were assessed according to the WHO criteria. Thus, a complete response was defined as disappearance of all disease on two measurements separated by a minimum of 4 weeks. A partial response required a greater than 50% decrease in the sum of the product of the bidimensional measurements of all measurable lesions documented by two measurements separated by at least 4 weeks. Stable disease was defined as a less than 50% decrease in bidimensional lesions and a less than 25% increase in the size of one or more measurable lesions. An increase of
Specific Toxicity Assessments Blood glucose (Glucotrend; Boehringer Mannheim, Mannheim, Germany) was monitored before the first dose of E7070 and every hour for 4 hours after the start of the first infusion. More frequent sampling was performed in the case of documented hypoglycemia until recovery. Blood glucose was monitored during subsequent cycles if hypoglycemia was detected after the first dose of E7070. Creatinine clearance was to be repeated if serum biochemistry revealed an increase in serum creatinine greater than grade 1 or greater than 1.5 times ULN.
Drug Administration
Dose Escalation Procedure In the absence of DLT, doses were escalated according to the following scheme: If no or minimal grade 1 toxicity was observed at cycle 1, doses were escalated in 100% steps. If grade 2 toxicity (other than alopecia, anemia, lymphopenia, and untreated nausea and vomiting) occurred at cycle 1, doses were escalated in 50% to 66% steps and rounded to one of the closest hundred. If grade 3 hematologic toxicity, DLT, or both were observed at cycle 1 in one of the first three patients entered at a specific dose level, a group of three additional patients was enrolled at that dose level. DLT occurring during the first cycle in more than 50% of patients (two or more of three patients and three or more of six patients treated at the same dose level) defined the MTD and led to the termination of dose escalation. The recommended dose for phase II study was defined as the dose immediately below the MTD (ie, the dose associated with a DLT in two or fewer of six patients at cycle 1). After identification of the MTD and the recommended dose in group A, further dose escalation was permitted in another cohort of patients (group B) who were expected to tolerate higher doses of E7070.
Plasma and Urine Pharmacokinetic Sampling and Assay The concentration of E7070 in plasma was measured using high-performance liquid chromatography (HPLC) with spectrophotometric detection (Notox, Hertogenbosch, the Netherlands) Calibration curves were linear between 0.02 and 50 µg/mL according to weighted (1/x2) linear regression. Within-batch (relative SD, 0.7% to 18.2%; relative error, -18.7% to +14.3%) and between-batch (relative SD, 3.1% to 18.8%; relative error, -8.7 to +0.7%) precision and accuracy were acceptable. The lower limit of quantification of E7070 was 25 ng/mL. Briefly, 0.5 mL of plasma was transferred into a 7-mL glass vial (LSC vial; Canberra Packard) supplemented with 1.0 mL of 0.1 M phosphate buffer solution (pH 5.0) and vortex mixed for 5 seconds. After the addition of 3 mL of diethylether, the container was closed and shaken for 10 minutes before centrifugation at 1,500 x g for 5 minutes. The upper layer was pipetted off and added to 200 µL of 99/1 diethylether/glycerol. The organic phase was evaporated to dryness under a stream of nitrogen at 30°C over approximately 20 minutes. This residue was dissolved in 200 µL of end solution. A 100-µL aliquot of this solution was injected onto the chromatographic system. The concentration of E7070 in urine was measured using HPLC with tandem mass spectrometry detection (API 300 mass spectrometer; Perkin Elmer/Sciex, Toronto, Canada). The calibration curve was linear from 0.2 to 200 ng/mL, and the lower limit of detection was 0.5 ng/mL. Five milliliters of urine was added to 2 mL of 1.0 M acetate buffer (pH 5.0) and vortex mixed before being loaded onto a solid-phase extraction cartridge containing 2 mL of methanol, 2 mL of water, and 2 mL of 1.0 acetate buffer (pH 5.0). The cartridge was flushed with 2.0 mL of 40/60 acetonitrile and acetate buffer 6.7 mmol/L (pH 5.0), dried with compressed air, and eluted with 1.5 mL of methanol/10 mmol/L NH4Ac. The eluate was evaporated to dryness under a stream of nitrogen at 55°C for approximately 25 minutes. The residue was dissolved in 200 µL of end solution. A 50-µL aliquot was injected onto the chromatographic system.
Pharmacokinetic and Pharmacodynamic Analyses The post-NONMEM graphical exploration and statistical analysis of parameters was performed using S-Plus package software (version 4.5 for Windows, release 2). Plasma concentration-time data were subjected to exploratory graphical presentation, descriptive statistical, and graphical analysis. Statistical comparisons between groups (nonparametric Mann-Whitney and Kruskal-Wallis tests) for studying pharmacokinetic interactions were performed using GraphPad InStat 3.00 for Windows 95 (GraphPad Software, San Diego, CA). A two-sided P value less than .05 was considered significant.
General The characteristics of patients entered onto this study are listed in Table 1. A total of 40 patients with a variety of advanced malignancies were entered. All but three patients had received prior chemotherapy. The median number of prior chemotherapy regimens was two. Thirteen patients had received previous radiotherapy. A total of 152 cycles of E7070 had been administered at doses ranging from 50 to 1,000 mg/m2 (Table 2). The median number of courses administered per patient was three (range, one to 14).
The predominant DLTs of E7070 were neutropenia and thrombocytopenia. No toxicity (or grade 1 toxicity) was observed at cycle 1 at dose levels I to III, allowing a rapid dose escalation. Grade 2 toxicity was observed at dose level IV (400 mg/m2), leading to the investigation of 600 mg/m2 for the next dose escalation (dose level V). At the dose of 600 mg/m2, only mild to moderate grade 1 to 2 toxicity was observed, allowing the exploration of 1,000 mg/m2 as the next dose level (dose level VI). Dose-limiting myelosuppression was observed in three of three patients treated at 1,000 mg/m2, ie, one chemotherapy-naive patient with renal clear-cell carcinoma, one breast cancer patient, and one patient with adenocarcinoma of unknown primary who received more than two prior lines of chemotherapy. One of these patients had concomitant grade 3 fever, grade 3 malaise, and grade 4 infection that required hospitalization and intravenous antibiotics. Thereafter, a dose reduction to an intermediate level of 800 mg/m2 (intermediate dose level, between 600 and 1,000 mg/m2 [dose level VII]) was performed. Of the first four patients treated at 800 mg/m2, two patients with colon cancer who received more than three prior lines of chemotherapy developed dose-limiting thrombocytopenia, neutropenia, or both, which were associated with grade 3 mucositis in one case. Thus the dose of 800 mg/m2 was considered to be the MTD of E7070 in this study for the first cohort of patients (group A). A dose reduction to 700 mg/m2 (intermediate dose level, between 600 and 800 mg/m2 [dose level VIII]) was performed. One among the first three patients entered at this dose level presented febrile, grade 4 dose-limiting neutropenia associated with grade 4 mucositis and grade 3 anorexia. This prompted us to include three more patients at this dose level. Two patients were informed and screened simultaneously in both centers and both were enrolled onto the study. Therefore, a total of seven instead of six patients were treated at this dose level. One of these four additional patients presented a dose-limiting thrombocytopenia. Patients with hematologic DLTs at this dose level had colorectal cancer previously treated with more than three lines of chemotherapy. Thus, since two among seven patients presented DLTs at this dose level, 700 mg/m2 was considered to be the recommended dose for further studies for group A patients. To investigate whether further dose escalation was possible in less heavily pretreated patients with limited tumor burden (group B), an additional six patients were selected on the basis of predefined inclusion criteria (see Patients and Methods) and treated with E7070 at the dose of 800 mg/m2. None experienced a DLT at this level. Subsequently, three group B patients received 1,000 mg/m2 of E7070. Two of these patients developed DLTs. In addition, two patients from group A treated at the dose of 1,000 mg/m2 who also met criteria for group B presented hematologic DLTs. Thus, in group B, the MTD was defined as 1,000 mg/m2 and the recommended dose for phase II study was 800 mg/m2. Considering that only a limited number of patients were included in this phase I trial at the recommended doses, caution regarding the tolerability of these doses for phase II study is required. A careful survey of hematologic toxicity of patients entering onto phase II will have to be implemented.
Hematologic Toxicity
Specific Toxicity Assessments No clinical symptoms were reported that were consistent with changes in intraocular pressure that would have necessitated a specific ophthalmologic examination. Neither symptoms nor significant changes in systolic and diastolic blood pressure and pulse rate were observed during and for 4 hours after the infusion of E7070 at any cycle. ECGs taken at the MTD did not show any significant change in heart rates, and no significant trend toward an increase in QTc intervals was observed. Four patients showed a small nonsymptomatic increase in the complexity of ventricular extrasystolic activity during the infusion of E7070. Four patients had evidence of grade 1 or 2 palpitation and/or tachycardia on day 8 after the first infusion of E7070. As expected, patient glucose levels varied throughout the study. Four separate episodes of hypoglycemia were recorded. A grade 3 episode of hypoglycemia that lasted a few minutes occurred during the first hour after the first infusion of E7070 in one patient treated at dose level I. This event was not associated with clinical symptoms of hypoglycemia, was immediately reversible, and did not recur during subsequent doses. This was not considered to meet the criteria for DLT. Two other episodes of reversible nonsymptomatic grade 2 hypoglycemia were reported at dose levels I and IV, and one episode of grade 1 hypoglycemia was observed at dose level II. No episodes of hypoglycemia occurred at doses greater than 400 mg/m2. Hypoglycemia was predominantly reported after the first infusion of E7070, and no clear dose-dependent relationship was observed.
Other Nonhematologic Toxicity
Interaction With Oral Anticoagulants No significant modification of coagulation tests, including the activated partial thromboplastin time, was observed in patients after E7070 therapy. However, one 56-year-old patient with an advanced colorectal carcinoma who was treated with E7070 800 mg/m2 received concurrent acenocoumarol 1 to 3 mg daily for a deep vein thrombosis of the left leg. The patient’s baseline international normalized ratio (INR) was 1.82 but increased to 12.3 1 week after the patient received E7070. Acenocoumarol was discontinued and the patient was treated with intravenous vitamin K. The INR returned to normal within 1 week. When the patient was rechallenged with a second course of E7070, a similar increase in INR was observed. This observation indicates that an interaction exists between E7070 and acenocoumarol whereby its anticoagulant activity is potentiated by concomitant E7070 treatment. No other patient received oral anticoagulants during the study.
Pharmacokinetic Analysis
Response Twenty-seven patients were assessable for tumor response. No objective responses were observed. Fourteen patients had stable diseases lasting 2 to 13 months as their best response. None of these patients required palliative radiotherapy. Among them, six patients (treated at 800 mg/m2, 600 mg/m2, and 400 mg/m2 in one, two, and three cases, respectively) with documented tumor progression in the 3 months preceding study entry had 6-month tumor stabilization. One patient with metastatic melanoma and one patient with clear-cell carcinoma of the kidney presented 6-month tumor stabilization. Two patients with liver metastasis from a colon cancer that previously progressed under fluorouracil/folinic acid, irinotecan, and/or oxaliplatin chemotherapy experienced 6-month and 8-month tumor stabilization. A further 6-month stabilization period was noted in a patient with a pulmonary metastasis from a slow-growing epithelial cancer of the thymus previously treated with anthracycline, cisplatin, and etoposide. A patient with slow-growing malignant paraganglioma experienced 11-month tumor stabilization.
In the past decade, CDKs have been shown to play key roles in many human cancers and have been identified as novel targets for anticancer therapies.2,5,6,20 The most recent CDK inhibitors to be tested in the clinic are flavopiridol21,22 and the staurosporine analog UCN-01. Flavopiridol is a natural rohitukine-derived flavonoid that binds to the adenosine triphosphate–binding pocket of cdk1, cdk2, and cdk4 and causes cell-cycle arrest in both the G1 and G2/M boundaries.21,22 In clinical trials, the DLT of flavopiridol was diarrhea and, at higher doses, reversible hypotension and a proinflammatory syndrome.23-28 UCN-01 is a potent inhibitor of several protein kinase C isoenzymes that inhibits cdk1 and cdk2 at high concentrations. In vitro, UCN-01 produced an indirect activation of the cdk1/cyclin B complex abrogating the G2 checkpoint, thus promoting early entry into mitosis and subsequent apoptosis.29-31 In clinical trials, the toxicity of UCN-01 was characterized by nausea and vomiting, symptomatic hyperglycemia, and hypoxemia.3,32 Although both compounds possess different mechanisms of action and toxicity profiles, both induced durable partial responses and tumor stabilization in a variety of tumor types, including non-Hodgkin’s lymphoma, kidney cancer, gastric cancer, melanoma, and sarcoma. Although the optimum doses and schedules for these agents have yet to be defined, these studies demonstrate that pharmacologic CDK inhibitors can regulate tumor growth in vivo.3 E7070 is a novel sulfonamide that was selected from a library of compounds containing an indoyl-benzenesulfonamide moiety on the basis of its antiproliferative effects.8 Unlike flavopiridol and UCN-01, which interact directly with CDKs, E7070 modulates cell-cycle progression via indirect pathways, such as p53 and p21.33-35 Although E7070 exhibits several chemical and cytotoxic similarities to chloroquinoxaline sulfonamide, this study suggests that its toxicity profile is less severe and more predictable. Despite intensive monitoring for cardiac arrhythmias, no consistent modification of the cardiac rhythm or alterations in blood pressure were detected. Similarly, although several episodes of transient hypoglycemia were reported in some patients at doses below 600 mg/m2, no clear dose-response effect was seen and hypoglycemia was not reported either at or above the recommended safe dose for future studies. Instead, the DLTs of E7070 were reversible neutropenia and thrombocytopenia.
Grade 3 or 4 neutropenia and thrombocytopenia were reported only in patients treated with doses In this study, we applied conservative definitions of MTD and recommended doses, such as those classically used for cytotoxic agents. This led us to recommend relatively high doses of E7070 with an estimated risk of severe toxicity of approximately 30% in phase II trials. We considered this approach to be feasible because the toxicity profile of E7070 was comparable to that of classical cytotoxic drugs with DLTs mainly consisting of reversible neutropenia and thrombocytopenia. This approach might not be valid for other compounds that induce nonhematologic toxicity. In addition, development of noncytotoxic drugs has brought new concepts for which activity is not close related to the highest dose-intensity. This concept has proved to be valid for very specifically target-oriented compounds. So far, this approach has not been proven to be efficient for cell-cycle inhibitors. In addition, effects of those agents on the cell cycle of hematologic stem cells, capable of inducing neutropenia and thrombocytopenia, might be surrogate end points of biologic activity in tissue. For example, the dose of 600 mg/m2 in our study was associated with no neutropenia and thrombocytopenia, which would indicate that concentrations of the drug in bone marrow were below those capable of inducing reversible hematologic stem-cell–cycle arrest. Considering this dose for further phase II trials would have potentially induced the risk of underestimating the dose to be recommended for phase II studies. On the other hand, the recommended doses of this compound shall be regarded as high. When one considers that only a limited number of patients were included in this phase I trial at the recommended doses, caution regarding the tolerability of these doses for phase II study is required, and a careful survey of hematologic toxicity of patients entering onto phase II will be implemented. In addition, although no cardiac toxicity was reported in this study, phase I trials cannot identify rare events and/or cumulative cardiac toxicity that could appear when larger cohorts of patients are treated. Therefore, careful cardiac monitoring during the phase II program will be performed to confirm the safety of E7070.
The majority of other toxicities seen were mild to moderate in severity. Nausea and vomiting were largely restricted to patients who had experienced severe nausea and vomiting with previous chemotherapy and were easily treated with metoclopramide or 5-hydroxytryptamine antagonists. Systematic prophylaxis was unnecessary for patients receiving E7070 doses Interestingly, three other phase I trials reached conclusions that were very similar to ours. Punt et al36 recently reported the results of a phase I trial using daily-for-5-days infusion every 3 weeks. E7070 was shown to induce myelosuppression consisting of febrile neutropenia and thrombocytopenia as primary DLTs. Similar conclusions were obtained in other phase I trials investigating a weekly infusion schedule and a protracted continuous-infusion schedule. No cardiac toxicity was reported in the overall phase I program. The recommended doses of the daily-for-5-days, weekly, and protracted infusion schedules were 130 mg/m2, 400 mg/m2, and 96 mg/m2, respectively. Calculated dose-intensities at recommended doses were 267.7, 267.7, 333.3, and 216.7 mg/m2/wk in the every-3-weeks, daily-for-5-days, weekly, and protracted infusion schedules, respectively. Given these data, our schedule was selected for phase II trials investigating the activity of E7070 as a single agent. Since cell-cycle modulators are drugs likely to be optimally used in combination with other anticancer agents, alternative schedules might also be regarded as potentially interesting for combination chemotherapy.
As shown in Fig 3, plasma concentrations of E7070 during the 48 hours after the infusion at the recommended doses of 700 mg/m2 (group A) and 800 mg/m2 (group B) were above 20 µg/mL and 30 µg/mL, respectively. In preclinical models, E7070 delayed the transition from the G1 to the S phase of the cell cycle in a dose-dependent manner. At lower concentrations, ranging from 0.41 to 3.7 µg/mL and 3 to 10 µg/mL for 24 hours, a delay in the G1-S transition and cell-cycle arrest in G1 was observed in P388 murine leukemia cells and human HCT-116 colon cancer cells, respectively.33-35 At concentrations ranging from 3 to 30 µg/mL for 48 hours, DNA fragmentation and cell death were observed in human HCT-116 cancer cells. Flow cytometry analysis showed an increase in G0-G1 and a decrease in S phase populations in human A549 non–small-cell-lung cancer cells treated with E7070 at concentrations ranging from 20 to 100 µg/mL for 24 hours.37 Longer exposure of 48 hours increased the G2-M phase fractions. Interestingly, 72-hour exposure to E7070 20 µg/mL inhibited the phosphorylation of Rb, decreased expression of cyclin A, B1, CDK2, and CDC2, suppressed the catalytic activity of CDK2, and induced the expression of p53 and p21 as measured by Western blot analysis.37 Although, plasma concentrations only roughly reflect concentrations in tumor tissues, pharmacokinetic data of E7070 suggest that biologically active concentrations (ie, capable of blocking cell cycle) could be obtained in patients at recommended doses. Unfortunately, in this study no translational surrogate end point of biologic activity is available. Measurement of biologic markers in peripheral-blood mononuclear cells, skin, mucosal tissues, and tumor tissues using validated methods might be crucial in the future to more rationally recommend doses of cell-cycle agents such as E7070. At doses of E7070 greater than 400 mg/m2, there was a disproportional increase in AUC0- We found evidence of a clinically significant drug interaction between E7070 and acenocoumarol. This may be due to either inhibition of hepatic drug-metabolizing enzymes by E7070 or the displacement of acenocoumarol from protein-binding sites. Intensive monitoring of INR will be necessary in patients receiving concomitant oral anticoagulation in subsequent studies with E7070. Although no objective response was seen, minor responses and tumor stabilizations were observed in some patients whose disease progressed under prior chemotherapy regimens. Prolonged disease stabilization lasting more than 6 months was observed in six patients previously treated with chemotherapy who had evidence of tumor progression before they received E7070. Objective responses were also reported in other phase I studies using different schedules of E7070 administration in patients with ovarian and breast cancer associated with prolonged tumor stabilization in patients whose previous chemotherapy failed.38 In summary, we have shown that E7070, a small molecule that interacts with the cell cycle, has a safe toxicity profile in patients with advanced cancer, with DLT consisting of reversible neutropenia and thrombocytopenia. As indicated above, this compound belongs to a new family of small molecules that presented unique anticancer properties in the NCI COMPARE program. Interestingly, the compound was capable of inducing cytostatic effects characterized by prolonged tumor stabilization and some cytotoxic effects with partial responses in the phase I program. However, several issues still have to be addressed. For example, the drug development program was based on classical toxicity parameters for the recommendation of doses for phase II trials. This issue might need to be revisited using surrogate end points of biologic activity (such as Rb phosphorylation and p21 and p53 expression) when those data become available and are validated for translational research. Furthermore, tumor types and individual patients who might benefit from treatment with cell-cycle modulators have to be more clearly defined. Finally, it is likely that cell-cycle modulators will be more rationally developed in combination with classical cytotoxic drugs and radiotherapy. Currently, the phase II exploratory program with E7070 given as a single agent is investigating the antitumor property of the drug in patients with non–small-cell lung, colon, breast, ovarian, and renal cell carcinomas as well as melanoma and lymphoma. Time to tumor progression and objective response rates will be classical end points for evaluation of the antitumor activity. Further studies will be conducted shortly using this administration schedule to explore the activity and to determine the safety profile of E7070 in combination with other anticancer drugs in a variety of cancers.
Sponsored by Eisai Ltd, London, United Kingdom. We acknowledge the assistance of the nursing staffs in pharmacokinetic sampling and Murray Yule, MD, for assistance in preparing the manuscript.
This article was published ahead of print at www.jco.org.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
), terminal half-life (t1/2), systemic clearance (Cl), steady-state volume of distribution (Vdss), mean residence time, and renal clearance (ClR). 
) of Cmax, AUC0-
