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© 2001 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of Ecteinascidin-743, a New Marine Compound, Administered as a 24-hour Continuous Infusion in Patients With Solid TumorsFrom the Hôpital Paul Brousse, Villejuif; Cvitkovic et Associés Consultants, Bicêtre; and Centre René Huguenin, Saint Cloud, France; Pharma Mar S.A. Clinical Research and Development, Madrid, Spain; and Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slotervaaart Hospital, Masteram, the Netherlands. Address reprint requests to E. Cvitkovic, Hôpital Paul Brousse, 12-14 Boulevard Paul Vaillant Couturier, 94800 Villejuif, France; email: e.cvitkovic{at}cvitkovic-ac.fr
PURPOSE: To define the maximum-tolerated dose (MTD) and the phase II recommended dose (RD) of ecteinascidin-743 (ET-743) given as a 24-hour continuous infusion every 3 weeks to patients with treatment-refractory solid tumors. PATIENTS AND METHODS: Fifty-two patients received a total of 158 cycles of ET-743 at one of nine dose levels (DLs) ranging from 50 to 1,800 µg/m2.
RESULTS: The MTD was defined as 1,800 µg/m2 (DL 9), and the phase II RD was 1,500 µg/m2 (DL 8) for moderately pretreated patients with performance status (PS) 0 to 1 and good hepatobiliary function. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were severe at the MTD (1,800 µg/m2) in 94% and 25% of cycles, respectively. At the RD (1,500 µg/m2), neutropenia and thrombocytopenia were present in 33% and 10% of cycles, respectively. Transient acute elevated transaminase levels occurred in almost all cycles and was severe in 38% of cycles. Severe toxicities and DLTs were observed in patients with poor PS or abnormal liver function or who had received a large number of previous chemotherapy regimens. Antitumor activity was observed at the three highest DLs, including three partial responses (breast cancer, osteosarcoma, and liposarcoma), and four patients (all with progressing soft tissue sarcomas) had stable disease lasting CONCLUSION: The RD for a 24-hour continuous intravenous infusion of ET-743 is 1,500 µg/m2, with the most prevalent DLTs being hematologic. Patients with minor baseline hepatobiliary function abnormalities have a higher likelihood of severe hematologic toxicities and AUC-related DLTs, requiring dose adjustments or delays.
ECTEINASCIDIN-743 (ET-743) is isolated from the Caribbean marine tunicate Ecteinascidia turbinata.1 This tetrahydroisoquinolone alkaloid2 is a guanine-specific minor groove binding agent3 specific for alkylation of GGC and AGC sequences of DNA. It blocks the cell cycle in late S and G2 phases,4 making it a suitable agent for use in cancer therapy. ET-743 also affects the organization and assembly of the microtubule network, although it does not seem to interact directly with tubulin.5 Sensitivity and NCI COMPARE profiles determined from in vitro studies are similar to those obtained for morpholino-containing DNA intercalators and DNA binding agents.6 Preclinical studies have shown ET-743 activity in several solid tumors, showing preferential activity in ovarian, breast, and non–small-cell lung carcinomas; melanomas explanted from patients; and renal human cancer cell lines.7,8 Antitumor activity was also reported in explants of human tumor samples chemically resistant to alkylator agents (cyclophosphamide, doxorubicin, and cisplatin) and tubulin-interactive agents (vinblastine and paclitaxel).7 Its cytotoxicity in vitro seems to correlate with the expression of P-glycoprotein, the multidrug resistance-1 gene product (MDR1). Interestingly, Jin et al9 showed that ET-743 inhibits MDR1 transcription (by multiple inducers) without affecting constitutive MDR1 transcription. Preclinical induction of secondary resistance has been difficult to elicit and has been shown to correlate with MDR1 induction.10 Administration of ET-743 at the maximum-tolerated dose (MTD) for different time exposures in in vivo studies in mice induced long-lasting, complete regressions in non–small-cell lung carcinomas (LXFL529), melanomas (MEXF 89), and ovarian (HOC22) chemosensitive human xenografts.11-13 Strong inhibition was observed in all tumor models at half the MTD, with moderate activity at a quarter of the MTD. Several studies indicate a time exposure dependency, showing increased ET-743 activity with longer exposure.8,14 In addition, ET-743 induced a partial tumor regression in a chemoresistant (although marginally cisplatin-sensitive) ovarian carcinoma xenograft (HOC18).13 Preclinical toxicology studies showed that the target organs were bone marrow and liver and that the main toxicities were leukopenia, anemia, a reversible increase in liver function tests, and evidence of cholangitis.8 The proposed starting dose of 50 to 60 µg/m2 for a human phase I trial was based on toxicology studies that determined the mouse 10% lethal dose as 60 µg/m2, one tenth of the rat MTD as 54 µg/m2, and one third of the dog no toxic level as 66 µg/m2. By using these preclinical data, we conducted a phase I study in patients with solid tumors to determine the safety, toxicity, and pharmacokinetic (PK) parameters of ET-743 given as a 24-hour continuous infusion every 3 weeks. The 24-hour continuous infusion regimen was chosen on the basis of both the preliminary PK data showing a very short half-life of ET-743 in rodents and toxicology data indicating that dose-limiting toxicities (DLTs) may be maximum plasma concentration (Cmax) related.
Patient Population Patients were eligible for inclusion if they had a histologically or cytologically confirmed advanced solid tumor that was not amenable to established forms of treatment. Patients had to be aged between 18 and 75 years and have an Eastern Cooperative Oncology Group (ECOG) performance status (PS)  2. In addition, patients were required to have a neutrophil count  2.5 x 109/L, a platelet count 100 x 109/L, hemoglobin levels of 10 g per 100 mL, normal hepatic function (bilirubin < 25 µmol/L [1.5 mg/dL], transaminases and alkaline phosphatase [AP] the upper normal limit), and normal renal function (serum creatinine 120 µmol/L [1.4 mg/dL]). Patients were ineligible for the study if they had received any radiotherapy, chemotherapy, immunotherapy, or growth factor administration in the 4 weeks before study entry, a bone marrow transplant, or intensive chemotherapy with stem-cell support. Pregnant or breast-feeding women were also ineligible, as were patients with a previous history of liver disease (eg, chronic active hepatitis or cirrhosis) and patients with clinical signs or evidence of brain involvement or leptomeningeal disease. Accrual expansion at the recommended dose (RD) was planned after establishing the MTD. Minor eligibility violations were then allowed by common agreement between the investigator and the sponsor, mostly with respect to liver function test baseline value limitations, to assess the impact of various inclusion criteria on the safety and tolerance of this agent and on PK and pharmacodynamic (PD) parameters. The protocol was approved by the ethics committee at the Bicêtre University Hospital (Kremlin-Bicêtre, France), and written informed consent was obtained from all patients before enrollment.
Treatment Plan
The MTD was defined as the maximum dose that resulted in a DLT in
PK Studies
Statistics
Patient Characteristics and Doses Administered Between May 1996 and June 1999, a total of 52 patients were treated with one of nine different DLs and were given a total of 158 treatment cycles. Patient characteristics are listed in Table 1. Most patients had an ECOG PS of 0 or 1. Colorectal tumors, sarcomas, breast tumors, and ovarian tumors were the most common tumors in treated patients. Patient distribution by DL is listed in Table 2. Three patients were treated at each of the first six DLs. At DL 7 (1,200 µg/m2), the first three patients developed transaminitis (grades 2 and 3); thus, two additional patients were treated with the same dose. Although these two patients experienced only grade 1 transaminitis, because the doses being used were similar to the active toxic dose in preclinical trials the dose was increased by only 25% (DL 8; 1,500 µg/m2). The first three patients treated at DL 8 did not show a DLT; thus, a 20% dose increase (DL 9; 1,800 µg/m2) was tested, and this dose was defined as the MTD after three of four patients experienced DLTs. Expansion of patient accrual at DL 8 (the RD) was implemented, as is customary in phase I trials, to better assess safety and PK/PD. Thus, after establishing DL 9 (1,800 µg/m2) as the MTD, 21 additional patients were treated at DL 8 (1,500 µg/m2) to elicit safety profile differentials according to disease extent and pretreatment characteristics.
Toxicity The first symptom observed was gastrointestinal toxicity. Moderate nausea was seen from DL 2 ( 100 µg/m2), and vomiting was seen from DL 5 ( 600 µg/m2). Nonetheless, in general, few vomiting episodes were seen, and these occurred between 6 and 10 hours after the initiation of perfusion and were resolved after symptomatic treatment. This toxicity was generally mild, without anorexia, and had no impact on patient food or liquid intake. At the MTD (1,800 µg/m2), grade 1 and 2 vomiting was observed in four of four patients in nine (56%) of 16 cycles ( Table 3). At the RD (1,500 µg/m2), grade 1 and 2 vomiting was seen in 11 (44%) of 25 patients in 19 (26%) of 73 cycles, and grade 3 vomiting was seen in three (12%) of 25 patients in four (5%) of 73 cycles. This toxicity was successfully treated and prevented with standard doses of hydroxytryptamine-3 blocking agonists. No other toxicity was observed at the first five DLs (50 to 600 µg/m2). Asthenia was reported in 17 (33%) of 52 patients, 15 of whom were treated at either DL 8 (1,500 µg/m2) or DL 9 (1,800 µg/m2). Typically, it lasted between 7 and 10 days after treatment and was very seldom severe or treatment limiting, in contrast to the results of another phase I trial with a shorter administration regimen.16 Because it is a subjectively evaluated variable that is difficult to quantify, the prevalence and severity of asthenia are largely dependent on the investigator’s assessment. No alopecia, renal dysfunction, or signs of cardiac or neurologic toxicity were seen.
The major form of toxicity was hematologic. At DL 9 (1,800 µg/m2), four patients (100%) experienced grade 4 neutropenia (lasting more than 5 days in the case of three patients), and one patient experienced febrile neutropenia ( Table 4). Grade 3 or 4 thrombocytopenia was observed in two (50%) of four patients, both of whom required platelet transfusions, and in four (25%) of 16 cycles. Thus, DL 9 (1,800 µg/m2) was considered the MTD, with severe neutropenia and thrombocytopenia being the DLTs.
At the RD (DL 8; 1,500 µg/m2), the 25 treated patients received a total of 73 cycles, with a median of two cycles per patient and a mean of 2.9 cycles per patient (range, one to six), with eight patients receiving four or more treatment cycles. All patients and cycles were assessable for safety. Neutropenia was the most commonly observed toxicity, with 28 (38%) of 73 of the cycles showing grade 3 or 4 toxicity (Table 3). This side effect was complicated (fever, infection, or both) in only two instances (two patients and two cycles). The nadir value occurred around day 13, the median duration of grade 3 to 4 was 7 days, and the median day of recovery to grade 1 was day 22. Furthermore, grade 4 neutropenia lasting more than 5 days was reported in seven patients (28%) and eight cycles (11%). Severe thrombocytopenia was also observed but was less frequent. It was seen in 28% of patients and 10% of cycles, with a median duration of 10 days. This toxicity was always observed concurrently with severe neutropenia. Four patients who experienced severe thrombocytopenia required platelet transfusions until recovery. Severe anemia was also reported at DL 8, with grade 3 present in 13 cycles (18%). RBC transfusions were required by 10 patients (in 11 cycles). It was also prevalent at mild levels (grade 1 to 2) in 79% of cycles. It is of interest that two patients (4%) in the study developed a long-lasting grade 4 neutropenia and thrombocytopenia. One patient (no. 31), treated at DL 9 (1,800 µg/m2), developed severe neutropenia (grade 3 to 4, lasting 21 days) with recovery to grade 1 at day 27 and concomitant severe thrombocytopenia (grade 3 to 4, lasting 28 days), with recovery to grade 1 at day 34. After a dose reduction to the DL below (DL 8; 1,500 µg/m2), the third cycle was well tolerated. The second patient (no. 43), treated at DL 8 (1,500 µg/m2), had the same toxicity after the second cycle. This heavily pretreated patient (nine previous chemotherapy lines) also had major liver involvement. She developed severe neutropenia (lasting 23 days) and severe thrombocytopenia (lasting 56 days), with recovery to grade 1 at days 35 and 68, respectively.
Biochemical hepatic toxicity was also apparent with a reversible mild to moderate (grade At the RD, transient, treatment-related, biochemical liver test changes in transaminases were observed in all patients, with grade 3 or 4 transaminitis occurring in 68% of patients and 38% of cycles (Table 3). Characteristically, major elevations in enzyme activity (ie, AST and ALT) usually started at day 2, peaked during the first week, and returned to the baseline value by day 15. However, three patients took longer to recover to baseline (two at day 29 and one at day 34). This may potentially have been caused by the fact that two of these patients, who also presented concomitant grade 4 neutropenia and infection, were receiving potentially hepatotoxic antibiotic treatment. It should also be noted that the third patient was receiving medication (fluoxetine) with potentially hepatotoxic side effects. These events were nevertheless considered to be treatment-related DLTs. Figure 1 shows the median and quartiles of AST at baseline and over the first three cycles for patients treated at the RD and grouped according to baseline AP values. It seems that for patients with normal AP baseline values, the elevation of transaminases is self-limiting and of minor importance in successive cycles (as observed at DLs 6 [900 µg/m2] and 7 [1,200 µg/m2]), whereas for patients with abnormalities in AP baseline values (which itself indirectly reflects the dynamics and volume of liver metastases), this elevation seems to be long lasting and persistent in successive cycles, probably because of the concomitant progressing liver metastatic disease.
Serum bilirubin elevation was first seen at DL 6 (900 µg/m2). However, it was usually mild, with grade 2 toxicity observed in three (11%) of 27 cycles administered at DLs 6 and 7 (1,200 µg/m2). At the MTD, patients experienced grade 2 hyperbilirubinemia in four (25%) of 16 cycles and grade 3 in one (6%) of 16 cycles (Table 3). At the RD, an increase in serum bilirubin was seen in 30% of 73 cycles, and was severe (grade 3 or 4) in 13 cycles (18%). AP elevation was a sporadic event, observed only at DL 8 (1,500 µg/m2), with two patients (8%) reaching grade 2 in three cycles (4%). This elevation reached grade 3 in a single treatment cycle (2%). Liver toxicity was concomitant with moderate (grade 1 or 2) asthenia in 10 (40%) of 25 patients and 18 (25%) of 73 cycles. Asthenia was severe (grade 3 or 4) in only two patients (8%) in two cycles (3%). It is of interest that the severity of transaminitis correlated with the occurrence of hematologic toxicity, and thus the grade of early peak transaminitis may be a predictor of subsequent severe hematologic toxicity. When grade 3 or 4 transaminitis was present (37 cycles) at the three highest DLs (1,200, 1,500, and 1,800 µg/m2), severe neutropenia was reported in 20 (54%) of these cycles. In comparison, when grade 0 to 2 transaminitis occurred (71 cycles), severe neutropenia was reported in only 23 cycles (32%; P = .039). Similarly, when grade 3 or 4 transaminitis occurred at these DLs, it was associated with severe thrombocytopenia in 10 cycles (27%). This was in contrast to grade 0 to 2 transaminitis, which was associated with severe thrombocytopenia in only two cycles (3%; P < .001). Whether this correlation originates mainly in specific patient, organ function, or disease pretreatment variables will, we hope, be elucidated with larger patient cohorts. Table 5 shows the frequency of hematologic and hepatic toxicities according to baseline biochemistry values. The occurrence of severe neutropenia and thrombocytopenia correlates with the presence of mild baseline AP abnormalities. Furthermore, DLTs correlated with AP baseline abnormalities, as is shown in Fig 2.
At the RD (DL 8; 1,500 µg/m2), 23 (48%) of 48 cycles were delayed, eight (35%) of them caused by hematologic toxicity (median number of days of delay was 4). This hematologic toxicity was neutropenia in five cases and simultaneous neutropenia and thrombocytopenia in three. The median dose-intensity was 494 g/m2/wk, with a given relative dose-intensity of 99%. The high dose-intensity observed at the RD correlates both with the fact that in 87% of instances the treatment delay was less than 1 week and with the fact that dose reductions were implemented in only three cycles. Table 6 shows characteristics of patients experiencing DLTs at either the MTD or the RD. In contrast with patients treated at DL 9 (1,800 µg/m2), those developing DLTs at DL 8 (1,500 µg/m2) had either poor PS, liver involvement (eight of 10 patients), or abnormal liver tests (nine of 10 patients) or were heavily pretreated (median number of regimens, five; range, one to nine). Patients treated at the RD who did not experience DLTs ( Table 7) had good PS, no liver involvement (14 of 15), normal liver function (nine of 15), and moderate pretreatment (median number of regimens, three; range, one to five). A multivariate analysis showed that liver involvement and liver function (AP) are significant predictive factors of DLT occurrence (P = .059 and P = .040, respectively).
On the basis of these observations, DL 8 (1,500 mg/m2) is considered to be the RD for patients with normal hepatobiliary function (on the basis of biochemical parameters), who are in good general condition, and who may have received low or moderate cytotoxic pretreatment.
Patient Responses
Furthermore, four patients with progressing soft tissue sarcomas at accrual achieved clinically meaningful disease stabilization lasting 3 months: one at DL 6 (900 µg/m2), two at DL 8 (1,500 µg/m2), and one at DL 9 (1,800 µg/m2).
PK/PD
The PK/PD study (presented here in brief because full details will be published elsewhere) showed that there is a correlation between the AUC and the grade of AST or ALT increase in a cycle (Spearman’s correlation coefficient [rs] for AST grade = 0.580, P < .001; rs for ALT grade = 0.367, P = .004). Weaker correlation were obtained for Cmax (AST rs = 0.415, P = .001; ALT rs = 0.362, P = .004). The grade of neutropenia and thrombocytopenia correlated with the AUC (neutropenia rs = 0.413, P = .001; thrombocytopenia rs = 0.495, P < .001). The grade of neutropenia did not significantly correlate with Cmax (rs = 0.190, P = .142), but there was a trend toward a statistically significant correlation between the grade of thrombocytopenia and AUC (rs = 0.250, P = .052). There were no significant correlations between the grades of nausea, vomiting, or fatigue and either AUC or Cmax. Treatment cycles complicated by DLTs had a significantly higher AUC (geometric mean 85.3 v 44.4 hours·µg/L, P = .002). When categorizing AUC into three areas (< 40, 40 to 70, and > 70 hours·µg/L), the likelihood of a DLT, a grade 4 thrombocytopenia, or a long (> 5 days) grade 4 neutropenia increased with increasing AUC, as listed in Table 10.
The PK/PD analysis showed that increasing AST/ALT liver toxicity correlates with increasing doses and AUC and that neutropenia correlates with Cmax and AUC. In some patients, extensive intrapatient variability was seen. For example, a 35-year-old female patient (no. 43) treated at DL 8 (1,500 µg/m2) had good tolerance to the treatment after cycle 1 but presented a severe toxicity at cycle 2, showing a correspondingly high AUC in cycle 2 (205 hours·ng/mL) compared with cycle 1 (60 hours·ng/mL). This patient was withdrawn from the study as a result of this toxicity. A 67-year-old male patient (no. 39) with bulky liver involvement, an external biliary drain, and borderline hepatic function was treated at DL 8. He developed severe neutropenia (grade 4) and had a correspondingly high AUC (105 hours·ng/mL) in the first treatment cycle, compared with the median AUC (57 hours·ng/mL) observed in the first cycle of the DL 8 patient cohort.
In this phase I dose-finding study, 52 patients were treated at one of a range of nine DLs. The MTD of ET-743 given as a 24-hour infusion every 3 weeks was determined as 1,800 µg/m2, and the RD was determined as 1,500 µg/m2 for low-risk patients, defined as those with no baseline hepatobiliary function test abnormalities, only moderate pretreatment, and good PS (PS 0 or 1). The major DLT was hematotoxicity (ie, neutropenia and thrombocytopenia). At the MTD, severe (grade 3 or 4) neutropenia was reported in 94% of cycles, and severe thrombocytopenia, in 25% of cycles. At the RD, severe neutropenia was reported in 38% of cycles, and severe thrombocytopenia, in 10% of cycles. These levels of hematotoxicity are comparable to those found with other agents recently approved for treatment of solid tumors, such as the taxanes18,19 or irinotecan.20,21 Furthermore, at the RD, these episodes of severe neutropenia or thrombocytopenia rarely persisted for more than a week and were usually not complicated (ie, febrile neutropenia, infection, and hemorrhage). Nevertheless, it is advisable that in future studies patients be monitored weekly for hematotoxicity, which generally appears approximately 10 days after dosing, with the nadir occurring around day 13. This hematotoxicity is clearly DL dependent. Grade 3 or 4 hematologic toxicity episodes were not experienced by any patients at any DL up to 1,200 µg/m2, compared with 52% of patients at 1,500 µg/m2 and 100% at 1,800 µg/m2. The fact that a 20% to 25% dose increase results in a 50% increase in the rate of this limiting toxicity, along with the observation that all responses occurred at the two highest DLs, points to a narrow therapeutic index of ET-743 when it is administered with this regimen. In light of the significant toxicity observed in patients treated at potentially effective doses and the evidence suggesting a differential risk for hematotoxicity according to the patient’s baseline condition, it would be advisable that patients who are to be treated with a dose of 1,500 µg/m2 be in a good general condition, have received only a moderate degree of pretreatment, and be free of biochemical liver abnormalities. For those who do not fit these criteria, and to further optimize dose recommendations for patients at high risk, a range of doses between 1,200 and 1,400 µg/m2 needs to be tested and their PK/PD relationships determined. It is important to note that at the RD, 48% of cycles were delayed, 35% of which were caused by hematologic toxicity, principally neutropenia. Most (87%) of these delays were shorter than 1 week. Furthermore, for neutropenia, the median day of recovery to grade 1 (at which time treatment could be recommenced) was 22 days. Thus, for some patients, it may be necessary to administer ET-743 every 4 weeks instead of every 3 weeks, especially in patients with one or more risk characteristics. Hepatotoxicity, reported as a transient increase in ALT and AST levels, was first seen at the dose of 900 µg/m2. At doses of 900 and 1,200 µg/m2, although ALT and AST levels were elevated, the severity of the toxicity decreased with successive cycles. At the MTD, elevated ALT and AST levels were reported for all patients in all cycles and were severe (grade 3 or 4) in 38% of cycles. At the RD, elevated ALT and AST levels were reported for all patients in all cycles and were severe in 38% of cycles. Nevertheless, there was a lower rate of grade 4 toxicity at the RD (7% of cycles) than at the MTD (19% of cycles), and more importantly, in all cases these toxicities were transient and reversible. Early elevations of AP and bilirubin after dose administration, which have been correlated with an enhanced risk of DLTs in subsequent cycles,22 may predict these toxicities. Patients who experienced severe transaminitis also developed neutropenia and thrombocytopenia in the same cycle. Thus, this particular toxicity may be useful for predicting the occurrence of severe hematologic toxicity. After the identification of potential toxicities in preclinical toxicology studies,8 we were particularly careful to document any signs of hepatotoxicity in this study. Thus, although the rate of hepatotoxicity seems elevated in comparison with other anticancer agents, it is important to take into account the fact that earlier studies with other commonly used anticancer agents often lack data on hepatotoxicity. A likely reason for the prevalence of hepatotoxicity is the frequency of its assessment in our trial (ie, twice weekly over the first 2 weeks after each dosing) and the prevalence of often bulky and rapidly progressing hepatic metastases. Other anticancer agents have for some time been recognized as being transiently and reversibly hepatotoxic. For example, methotrexate, despite recent evidence of up to 24% hepatotoxicity,23 has long been and remains widely used as a single-agent treatment in a high-dose regimen for osteosarcoma24 and as a common treatment for breast cancer in combination with cyclophosphamide and 5-fluorouracil.25 Similarly, transient hepatotoxicity has been reported for recently approved anticancer agents, such as raltitrexed (10% for grades 3 or 4)26,27 and docetaxel (20%).28 Most importantly, the present study elicited the first observations of clinical antitumor activity allowing for intensive continued clinical development. The thorough multicycle PK analysis shows linearity within the dose range studied, with large interpatient variability but only moderate intrapatient variability. Most importantly, the PK/PD relationship shows a correlation of the AUC with the rate and severity of hepatic toxicities. The rate of severe hematologic toxicity and DLTs was also correlated with AUC. The severity and duration to recovery of toxicities seem related to PK parameters, with the latter being linked to patient general status and liver function status; along with other characteristics, such as extent of pretreatment, these are probably covariates in morbidity likelihood. Further data and population PK analysis may better clarify the PK/PD relationship, leading to improved or alternate dosing guidelines, delivery schedules, or both. Three PRs were seen in this study, one at the MTD and two at the RD. The responding patient at the MTD had an extensive and treatment-refractory breast adenocarcinoma local recurrence. The two responses seen at the RD and meaningful stabilizations seen in treatment-refractory sarcoma patients are of particular interest because they confer differentiated preclinical activity profile and give hope for a family of diseases in which no new agents have been shown to be active in more than 20 years. After new response observations by our group,17 a large phase II program is currently underway in Europe and the United States to define further and confirm a role for ET-743 in this indication. In conclusion, we have determined the MTD of ET-743 administered as a 24-hour continuous infusion to be 1,800 µg/m2, with the DLTs being prolonged or complicated severe thrombocytopenia and neutropenia. Hematologic and hepatic toxicities are reversible and have no dose-cumulative characteristics. Characteristic transient liver function abnormalities are not dose limiting but are prevalent and often of a severe degree (grade 3 or 4) at both the RD and MTD. In these cases, they are associated with concomitant hematologic toxicities. The RD for phase II studies is 1,500 µg/m2 in patients with low or moderate pretreatment and without liver function biochemical abnormalities, administered every 3 weeks, although some patients may be better suited to an administration of once every 4 weeks. Patients with minor baseline liver function abnormalities have a higher likelihood of severe hematologic toxicities and DLTs requiring dose adjustments or delays. Clinical activity observed in breast cancer and sarcoma patients is being further defined in the currently ongoing clinical development program.
We thank Dr Sarah Mackenzie for her collaboration and help in editing the manuscript and Moshe Itzhaki for the statistical analysis.
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998; the European Society of Medical Oncology Meeting, November 1998; and the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
t) was calculated with the trapezoidal rule. The total AUC was calculated as the sum of AUC0
2 test or Fisher’s exact test as appropriate. Continuous variables were compared by using the paired t test, after log transformation if necessary. 
