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Journal of Clinical Oncology, Vol 23, No 24 (August 20), 2005: pp. 5484-5492 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.028 Ecteinascidin-743 (ET-743) for Chemotherapy-Naive Patients With Advanced Soft Tissue Sarcomas: Multicenter Phase II and Pharmacokinetic StudyFrom the Dana-Farber Cancer Institute, Harvard Medical School; Massachusetts General Hospital, Harvard Medical School, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; and Clinical Research and Development, PharmaMar, S.A., Madrid, Spain Address reprint requests to George D. Demetri, MD, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney St, Boston, MA 02115; e-mail: gdemetri{at}partners.org
PURPOSE: To evaluate the response rate, toxicity profile, and pharmacokinetics of ecteinascidin-743 (ET-743) as first-line therapy in patients with unresectable advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: Thirty-six patients with STS were enrolled onto the study between September 1999 and August 2000. Patients were treated with 1.5 mg/m2 of ET-743 given as a 24-hour continuous intravenous (IV) infusion every 21 days. Pharmacokinetic sampling was performed in 23 patients. RESULTS: One complete and five partial responses were achieved in 35 assessable patients for an overall response rate of 17.1% (95% CI, 6.6% to 33.6%). In addition, one patient had a minor response, leading to an overall clinical benefit of 20%. Neutropenia and transaminitis were the main grade 3 to 4 toxicities, which occurred in 33% and 36% of the patients. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11% to 41%) and 72% (95% CI, 59% to 88%), respectively. Total body clearance (L/h) was not significantly correlated with body-surface area (r = –0.28; P = .21). Mild hepatic impairment or the extent of prior cytotoxic therapy does not seem to contribute significantly to the high interpatient variability (49%) in the clearance of this drug. Severity of treatment-related toxicity was not correlated with pharmacokinetic variables. CONCLUSION: ET-743 demonstrates clinical activity as first-line therapy against STS with acceptable toxicity. Additional studies to establish empirical dosing guidelines may be necessary to improve the safety of the drug in patients with varying degrees of hepatic dysfunction and definitively establish the role of ET-743 for patients with these malignancies.
Soft tissue sarcomas (STSs) are rare tumors arising from connective tissues characterized by high morphologic and biologic heterogeneity, as well as by limited responsiveness to cytotoxic chemotherapeutic agents.1,2 Only two anticancer drugs, doxorubicin and ifosfamide, have consistently shown single-agent activity in advanced disease, inducing major responses in 20% to 30% of previously untreated patients.3-6 Therefore, continued efforts to evaluate new agents for clinical activity against this disease are absolutely needed. Ecteinascidin-743 (ET-743) is a natural marine product isolated from the Caribbean tunicate Ecteinascidia turbinata.7,8 ET-743 covalently binds to the minor groove of DNA,9,10 inducing a bend in the double helix toward the major groove.9,10 These structural changes are believed to interfere with the DNA binding of minor groove-interacting transcriptional factors such as nuclear factor-Y, which regulate, among others, genes involved in cell-cycle control such as cyclins B1 and B2.11 In concordance with this hypothesis, ET-743 has been shown to retard progression through the S phase of the cell cycle, eventually resulting in a G2/M block.8,12 The transcriptional activation of other nuclear factor-Y-regulated genes, such as MDR1, is also abrogated by ET-743 treatment in in vitro models.13 Finally, ET-743 interacts with the transcription-coupled nucleotide excision-repair (NER) machinery to induce lethal DNA strand breaks.14 In fact, defects in DNA-repair pathways have paradoxical effects on the antitumor activity of this drug: loss of mismatch repair does not affect its toxicity, loss of DNA-dependent protein kinase activity enhance it, and defects in NER confer resistance to ET-743. However, the precise sequence of events that transpire from drug-induced DNA damage to cell death remain to be elucidated. ET-743 exhibited potent preclinical antineoplastic activity against a wide range of cancer cell lines and xenograft models.8,15,16 In addition, objective responses were observed in early clinical trials in heavily pretreated patients with a variety of mesenchymal tumors, including osteosarcoma, leiomyosarcoma, mesothelioma, and melanoma, as well as carcinomas of the breast and ovary.17-21 These promising preclinical data and early signs of clinical activity have justified the ongoing development of this anticancer drug with a novel mechanism of action. Prior studies have demonstrated the activity of ET-743 in patients whose disease was progressive despite prior chemotherapy. However, the activity of this agent in patients whose sarcomas were never exposed to prior chemotherapy has not been studied before this trial. Here we describe a clinical trial conducted to evaluate the efficacy, tolerability, and pharmacokinetics of ET-743 given as a 1.5 mg/m2 24-hour continuous intravenous (IV) infusion to previously untreated patients with advanced STSs. In the phase I clinical trial of the 24-hour infusion schedule, the majority of patients in the expanded cohort treated with the 1.5 mg/m2 dose developed grade 3 to 4 transaminitis.18 Nevertheless, this dose was considered to be appropriate for phase II studies because the hepatotoxicity was transient and completely reversible, noncumulative on repeated dosing, and without any apparent clinical consequences. The severity of hepatotoxicity and hematologic toxicity, the latter of which was dose limiting for the 24-hour infusion schedule of ET-743, were both significantly correlated with the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of the drug.20,22 However, the pharmacokinetics of ET-743 also exhibited a relatively high degree of interpatient variability, with the coefficient of variation for the total body clearance (CL) exceeding 50% in two of the initial phase I trials.20,22 Although no significant associations between patient-related factors and CL were identified in the phase I studies, the acquisition of additional pharmacokinetic data during this and other phase II clinical trials of ET-743 was necessary to better understand the nature of the pharmacokinetic variability and its relevance to the safety of the drug. In particular, this clinical trial provided an opportunity to determine whether the magnitude of interpatient variability in the CL of ET-743 in chemotherapy-naive patients differed from previous studies in which the majority of patients were pretreated extensively with cytotoxic anticancer drugs.
Eligibility Criteria This study was conducted at The Dana-Farber Cancer Institute (Boston, MA), Massachusetts General Hospital (Boston, MA), and Memorial Sloan-Kettering Cancer Center (New York, NY). The protocol was approved by the institutional review boards of each participating center. Patients were required to have unresectable advanced or metastatic, histologically proven STS. Because of their clinically distinctive behavior, the following histologic subsets were excluded from the current study: gastrointestinal stromal tumors, rhabdomyosarcoma, osteosarcoma, carcinosarcoma, Kaposi's sarcoma, and mesothelioma. Other eligibility criteria included no previous chemotherapy for advanced disease; prior neoadjuvant/adjuvant chemotherapy only if concluded > 12 months before study entry; at least one bidimensionally measurable lesion; full recovery from any toxic effects of prior therapies; an Eastern Cooperative Oncology Group (ECOG) performance status of  1; age of  18 years; a minimum life expectancy of 3 months; a neutrophil count of 1.5 x 109/L; a platelet count of 100 x 109/L; creatinine of 132 µmol/L (1.5 mg/dL) or creatinine clearance of 40 mL/min; serum bilirubin and alkaline phosphatase less than or equal to the institutional upper limit of normal (ULN); AST and ALT of < 2.5x the ULN; and albumin of > 25 g/L. Pregnant or lactating women or patients with unstable medical or psychiatric illness, brain or leptomeningeal tumor involvement, or history of another neoplastic disease or poor compliance were excluded from study participation. All patients provided written informed consent.
Treatment Plan
The dose of ET-743 was reduced to 1.2 mg/m2 if any of the following toxicities occurred during the previous cycle of therapy: grade 4 neutropenia lasting
Assessment of Response and Toxicity
Pharmacokinetic Studies Individual patient plasma concentration-time data were analyzed by noncompartmental methods using routines supplied in the WINNonlin 1.1 software package (Scientific Consulting, Apex, NC). Estimated values of the pharmacokinetic parameters at each dose level are reported as the geometric mean ± SD of the values for the individual patients.26,27 The SD of the geometric mean was estimated by the jackknife technique.28 Parametric statistical tests using log-transformed values of the Cmax, AUC, or CL of ET-743 were performed to identify differences between subgroups of patients categorized according to demographic characteristics, toxicity, or response. P < .05 (two-tailed test) was considered to be significantly different.
Statistical Analysis All patients that received at least one cycle of therapy were considered assessable for toxicity and survival. Eligible patients were considered assessable for response if they had received a minimum of two cycles of treatment (ie, 6 weeks on study) and had at least one disease assessment performed at least 4 weeks after entering the study. Any patient who experienced early disease progression or died of progressive disease before response evaluation was also considered assessable for response. Patients that stopped treatment because of unmanageable toxicity were considered evaluable for response only if they had completed a minimum of two cycles of treatment. Two-stage conditional exact binomial 95% CIs30 were used to describe the distribution of the response rate. Progression-free and overall survival curves were estimated by using the Kaplan-Meier method.
Patient Population A total of 36 patients were enrolled onto the study between September 1999 and August 2000. A profile of the patient population is listed in Table 1. The predominant histologic subtypes were leiomyosarcoma and liposarcoma. The tumor bulk was > 5 cm in two thirds of the population and > 10 cm in 19% of the patients. Approximately half of the patients had received prior radiotherapy, but only 11% had received prior adjuvant chemotherapy.
Treatment Delivery The median number of cycles delivered per patient was two (range, 1 to 38), and nine patients (25%) received six or more chemotherapy courses. A total of 152 cycles of ET-743 was delivered to patients in this trial. The dose of ET-743 had to be reduced to 1.2 mg/m2 and 1.0 mg/m2 in 28% and 3% of the patients, respectively. Dose reductions were necessary because of hematologic toxicity (16% of the cases), alkaline phosphatase elevation (57% of the cases), and bilirubin elevation (27% of the cases). Treatment delays, however, were rather common (70% of the cycles) and were for the following reasons: hematologic toxicity (31 cycles), liver toxicity (10 cycles), and nontreatment-related reasons such as patient preference or schedule conflict (41 cycles). The median dose intensity of ET-743 received per patient was 449 µg/m2/wk (range, 290 to 500), which corresponds to 90% of the dose intensity planned.
Treatment Outcome
The reasons for study withdrawal were as follows: 29 patients were withdrawn because of disease progression (80.5%), one because of toxicity (2.8%), one because of maintained complete response (2.8%), one because of elective surgery to remove residual disease after a durable partial response (2.8%), and four because of patient choice or other nonmedical reasons (11.1%). The median follow-up at the time of this analysis for surviving patients was 25 months (range, 7 to 44 months). With this long follow-up, 31 patients have progressed and 26 patients have died. The estimated progression-free survival at 6 months was 24.4% (95% CI, 13% to 44%), and the estimated 1-year progression-free survival rate was 21% (95% CI, 11% to 41%; Fig 1). The overall survival rate at 1 year was 72% (95% CI, 59% to 88%; Fig 2).
Tolerability and Toxicity Profile Tables 3 and 4 summarize the main drug-related toxicities that were observed during this study. As expected, the most severe toxicities were primarily hematologic and hepatic. Grade 3 to 4 leukopenia and neutropenia occurred in 22% and 33% of the patients, respectively; however, no patient developed neutropenic fever. The other major adverse event was transaminitis, which in 34% (AST) and 36% (ALT) of the patients was of grade 3 or 4. These liver-enzyme elevations occurred within 3 to 4 days of drug administration and reverted to baseline values in all instances, never causing treatment discontinuation. Bilirubin and alkaline phosphatase elevations were at worst of grade 1 to 2 and occurred in 6% and 39% of the patients, respectively. However, in two patients a persistent alkaline phosphatase elevation on day 35 was the cause of study withdrawal. Aside from hepatotoxicity, emesis and fatigue were the most frequently occurring nonhematologic toxicities. Other toxicities were infrequent and manageable; particularly remarkable was the lack of alopecia, mucositis, or diarrhea associated with the study drug.
Pharmacokinetics Plasma specimens were obtained from 23 of the 36 patients during treatment with the initial 1.5 mg/m2 dose of ET-743. The data for one patient were not amenable to noncompartmental pharmacokinetic analysis. The mean AUC of ET-743 was 45.5 ± 20.7 ng · h/mL (range, 19.5 to 110.7 ng · h/mL) and the mean CL was 63.2 ± 30.8 L/h (32.6 ± 15.6 L/h/m2) for the 22 assessable patients. The mean value of the observed Cmax of the drug was 1.34 ± 0.61 ng/mL. CL (L/h) was not significantly correlated with body-surface area (r = –0.28; P = .21). There were no statistically significant differences in the mean AUC or Cmax between patients grouped according to sex, age ( 50 v > 50 years), and performance status. However, the four patients who were not pretreated with dexamethasone had a significantly greater (P = .01) mean AUC (75.9 ± 20.6 ng · h/mL) than the other 18 patients (40.6 ± 16.6 ng · h/mL). In contrast, the mean Cmax was not significantly different between these two groups (P = .09). It is also notable that grade 2 elevations in alkaline phosphatase during the first cycle of therapy, the greatest increase in this parameter that was observed, were limited to three of the patients who did not receive the dexamethasone antiemetic regimen. As depicted in Figure 3A, there was absolutely no suggestion of a correlation between AUC and the highest grade of any treatment-related toxicity that occurred during cycle one. Mean values of the AUC and Cmax in patients experiencing any severe toxicity (ie, grade 3 or higher) during the first cycle of therapy were not significantly different from those who did not. Similarly, AUC was not associated with either the highest grade hepatotoxicity (Fig 3B) or hematologic toxicity (Fig 3C). The mean AUC for the group of 12 patients who required a delay in treatment with the second cycle of therapy as a result of drug-related toxicity (42.4 ± 27.6 ng · h/mL) was similar to that for the 10 patients who did not require a treatment delay (49.4 ± 17.0 ng · h/mL). There was no significant difference in mean values of the AUC or Cmax of the drug in patients that showed evidence of therapeutic response in comparison to those with progressive disease.
This phase II study demonstrates for the first time the safety, tolerability, and antitumor activity of ET-743 in chemotherapy-naive patients with advanced STS. ET-743 induced objective responses in 17% of study patients, with a 1-year overall survival rate of 72%. These results are in the range of those observed with single-agent up-front therapy with the two cytotoxic drugs considered most active in this disease: doxorubicin and ifosfamide.3-5,31 The prognosis for most patients with advanced STS remains poor overall. Median survival does not generally exceed 1 year with the best available therapy. For patients with unresectable metastatic disease, chemotherapy is the mainstay of care. Despite intensive efforts performed over the past few decades to identify new effective therapies, doxorubicin and ifosfamide continue to be the only moderately active agents in this disease. Response rates of 20% to 25% have been reported with these drugs when used as single agents in chemotherapy-naive patients,3-5 although significantly lower rates (< 10%) have been demonstrated in more recent studies.31 Combining chemotherapeutic agents3,5,6 or increasing dose intensity32,33 can improve response rate and response duration. This benefit, however, should be factored against the higher toxicity associated with combination or dose-intense regimens, particularly considering the lack of benefit on survival of these therapeutic approaches.3,5,6,32,33 For patients who fail doxorubicin or ifosfamide therapy, the options are limited. In this context, the results obtained with ET-743 in this study justifies some prudent optimism. Indeed, ET-743 treatment induced durable control of disease in an important subset of patients, with progression-free survival rates exceeding 20% at 6 months as well as at 1 year. These data further support the hypothesis that ET-743 has clinically relevant antitumor activity against sarcomas, because progression-free survival has been suggested by the European Organisation for Research and Treatment of Cancer to be a valid indicator of drug efficacy in this type of tumors, more robust than the use of conventional size-based response criteria.34 Additional insights into the molecular mechanisms determining patient characteristics favoring tumor sensitivity to this new agent will help to prospectively select the subset of patients more likely to benefit from ET-743 therapy. Several lines of study have shown that polymorphisms in genes involved in nucleotide synthesis and DNA repair, as well as in drug metabolism, may contribute to interpatient variability in the efficacy and toxicity of many chemotherapy agents. ET-743 is a DNA minor groove–binding agent that affects transcriptional regulation in a promoter-dependent manner and paradoxically requires intact cellular machinery of transcription-coupled NER to induce cytotoxic effects. The study of endogenous polymorphisms of genes involved in DNA repair and their possible relationship to the antitumor activity and toxicity profiles of ET-743 in patients may be a powerful tool to optimize the clinical application of ET-743 therapy. Although tumor responses were observed in a number of different sarcoma subtypes, the predominant histology was liposarcoma. Nine patients with liposarcoma were included in the present study, one third of whom responded to therapy. All of the responders were of the myxoid/round-cell subtype. Similar findings were observed in our prior study conducted in patients whose disease progressed despite prior conventional chemotherapy.35 Whether ET-743 is a drug with remarkable activity against liposarcoma or whether this histologic subtype is particularly responsive to cytotoxic agents in general, as has been suggested in some studies,36 remains to be elucidated. In fact, tumor responses were observed in other different histologic subtypes as well, including leiomyosarcoma, fibrosarcoma, and synovial cell sarcoma. Also noteworthy was the manageable toxicity profile of ET-743 in our study population. Indeed, grade 3 to 4 neutropenia occurred in 33% of the patients, and it was never complicated by fever; other severe hematologic toxicities were uncommon. Slightly more than one third of the patients experienced grade 3 to 4 transaminitis, which was reversible in all instances and did not have any major clinical consequences. In addition, toxicities were noncumulative, and there were no toxic deaths. This toxicity profile compares favorably with that preliminarily reported in other clinical trials with this agent,18,37-39 in which severe neutropenia and transaminitis were reported in up to two thirds of the study population. One possible explanation for this discrepancy may be that, in our study, fairly strict liver-function test criteria were used for both study entry and re-treatment with additional cycles of ET-743. These criteria were implemented after a pooled analysis of several hundred patients treated with ET-743 showed that certain biochemical parameters, such as increased baseline bilirubin or intercycle alkaline phosphatase elevations, reliably predicted the incidence of severe toxicities.37 In addition, the majority of patients in our study received dexamethasone as antiemetic prophylaxis, which has been shown to decrease the incidence of severe toxicity in ET-743-treated patients.23 Finally, it should be noted also that 89% of the patients enrolled had never received chemotherapy before study entry. The plasma pharmacokinetics of ET-743 in the patients evaluated in this study was quite similar to that described for the expanded cohort of 25 patients treated with this same dose during the phase I trial of the 24-hour infusion schedule as well as two recently reported phase II studies of this dosing regimen in patients with advanced STS and osteosarcoma that had progressed during prior chemotherapy.35,22,40 There was close agreement between the mean CL of ET-743 determined in this phase II study (63.2 ± 30.8 L/h), the phase I trial (59 ± 31 L/h), and the other phase II trials (35.6 ± 16.2 and 31.3 ± 14.7 L/h/m2). Furthermore, interpatient variability in the CL of ET-743 in the group of chemotherapy-naive patients evaluated in the present study (49%) was comparable with that for the three reported clinical trials involving heavily pretreated patients, which ranged from 46% to 53%. Patients in the phase I trial were not only heavily pretreated, but hepatic-function requirements for entry into the study were much less restrictive than those adopted for this and the other two phase II trials.18,35,40 Thus, it does not seem that the extent of prior treatment with cytotoxic anticancer agents or moderate hepatic impairment contributes to the high interpatient variability in the CL of this drug. Patient characteristics had no apparent influence on the pharmacokinetics of ET-743, in agreement with findings of the phase I trial and a pooled analysis of data from several phase II trials of ET-743.22,23 The only factor identified in this study that seemed to contribute to interpatient variability in the CL of ET-743 was associated with the dexamethasone antiemetic regimen. There was a significant difference between the mean AUC in patients depending on whether they were pretreated with dexamethasone, with the AUC in all four of the patients who did not receive dexamethasone (range, 58.2 to 110.7 ng · h/mL) being greater than the mean AUC for the entire cohort of 22 patients (45.5 ± 20.7 ng · h/mL). However, the contribution of this effect to interpatient variability in the CL of ET-743 was relatively minor; the coefficient of variation decreased by only 5.1%, from 48.7% to 43.6%, after excluding the subset of patients who did not receive the dexamethasone antiemetic regimen from the calculation of the mean CL (70.2 ± 30.6 L/h). There was no evidence of a relationship between the AUC or Cmax of ET-743 and the severity of toxicity experienced during the first cycle of therapy or response to treatment. Similar results were reported for the phase II trials of ET-743 in previously treated STSs and osteosarcoma.35,40 In contrast, distinct relationships between these pharmacokinetic variables and toxicity have been demonstrated in phase I clinical trials of the drug given as a 24- or 72-hour continuous IV infusion.20,22 Thus, whereas toxicity in response to treatment with the drug is significantly correlated with the magnitude of pharmacokinetic variables indicative of systemic exposure to the agent over a broad range of doses, these correlations are not at all evident among patients receiving the same dose. In other words, variability in the CL of ET-743 or its Cmax does not offer an explanation to account for the development of severe toxicity and differential tolerability to this agent. In this context, the underlying rationale for pharmacokinetic dose individualization to improve the safety of the drug is absent. At this point in the clinical development of ET-743 as an anticancer drug, several hundred patients have been treated with a dosage of 1.5 mg/m2 given as a 24-hour continuous IV infusion, and the only correlates that have shown any predictive value for severe toxicity are pretreatment liver-function tests, including serum transaminases and alkaline phosphatase.18,23 Even relatively minor elevations in any baseline liver-function test above the ULN seems to predispose patients to the development of grade 3 to 4 toxicity independent of the CL of the drug.23 The ability to use ET-743 with an acceptable margin of safety in patients with varying degrees of hepatic dysfunction may require additional clinical trials to establish empirical dosing guidelines. In conclusion, the results of the current study indicate that ET-743 shows promise as an effective and tolerable new drug for the treatment of patients with STSs. Additional investigation of this agent alone or in combination with other cytotoxic drugs such as doxorubicin, which has shown to be synergistic with ET-743 in preclinical models both in vitro41 and in vivo,41,42 is warranted and currently ongoing. Shorter infusion schedules, such as 3-hour IV infusions, are also being assessed in other studies that aim to optimize patient convenience. Additional trials are ongoing to define more precisely the role of ET-743 in the treatment of patients with advanced STSs.
Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) a $100,000 (N/R) Not Required
Supported in part by research support from PharmaMar, S.A. (Madrid, Spain) and from grants from the Leslie's Links Foundation and the Quick Family Sarcoma Research Fund. R.G.-C. was supported in part by a grant from the Ministerio de Educacion y Cultura (Spain). Presented most recently at the 37th Annual Meeting of the American Society of Clinical Oncology, May 12-15, 2001, San Francisco, CA (preliminary results). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
