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Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients With Progressive Sarcomas of Soft Tissues Refractory to Chemotherapy

From the Dana-Farber Cancer Institute and Massachusetts General Hospital, Harvard Medical School, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; and Clinical Research and Development, PharmaMar, Madrid, Spain.

Address reprint requests to George D. Demetri, MD, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Shields Warren Bldg, Room G530, 44 Binney St, Boston, MA 02115; e-mail: gdemetri{at}partners.org

	ABSTRACT

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PURPOSE: To assess the efficacy of the marine-derived alkaloid ecteinascidin 743 (ET-743) in patients with soft tissue sarcomas that progressed despite prior conventional chemotherapy and to characterize the pharmacokinetic profiles of ET-743 in this patient population.

PATIENTS AND METHODS: Thirty-six previously treated soft tissue sarcoma patients from three institutions received ET-743 as a 24-hour continuous intravenous (IV) infusion at a dose of 1,500 µg/m² every 3 weeks. Pharmacokinetic studies were also performed. Patients were restaged every two cycles for response by objective criteria.

RESULTS: Objective responses were observed in three patients, with one complete response and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Two minor responses (43% and 47% tumor reduction) were observed, for an overall clinical benefit rate of 14%. The predominant toxicities were neutropenia and self-limited transaminitis of grade 3 to 4 severity in 34% and 26% of patients, respectively. The estimated 1-year time to progression and overall survival rates were 9% (95% CI, 3% to 27%) and 53% (95% CI, 39% to 73%), respectively. The maximum observed plasma concentration and total plasma clearance of ET-743 (mean ± standard deviation), 1.04 ± 0.48 ng/mL and 35.6 ± 16.2 L/h/m², respectively, were consistent with previously reported values from phase I studies of the drug given as a 24-hour IV infusion.

CONCLUSION: ET-743 is a promising new option for the management of several histologic subtypes of sarcoma. Durable objective responses were obtained in a subset of sarcoma patients with disease progression despite prior chemotherapy. Additionally, the relatively high survival rate noted in this series of previously treated patients further justifies development of this agent.

	INTRODUCTION

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Sarcomas of soft tissue represent a heterogeneous family of malignancies of mesenchymal origin that account for approximately 1% of adult neoplastic diseases diagnosed annually in the United States.¹ Although the majority of patients present with a clinically localized tumor, 30% to 60% will eventually develop local recurrence or metastatic disease.^2,3 Once the tumor has progressed beyond surgical resectability, the disease is nearly always incurable.^2,3 The median survival of patients with unresectable sarcomas of soft tissues is approximately 1 year. Patients with unresectable sarcoma have pressing needs for new effective therapeutic options.

Doxorubicin and ifosfamide represent the two most active conventional agents in the treatment of advanced soft tissue sarcomas. Prospective studies of these drugs administered as single agents to sarcoma patients with no prior chemotherapy have demonstrated response rates ranging from 11% to 30%.^4-6 Other less active drugs include dacarbazine,⁷ epirubicin,⁸ cyclophosphamide,⁵ or platinum compounds,^9,10 with objective responses documented in less than 20% of treated patients. Newer cytotoxic agents introduced in the 1990s, such as the taxanes,^11,12 topotecan,¹³ vinorelbine,¹⁴ and gemcitabine,¹⁵ have also been evaluated in patients with advanced soft tissue sarcomas with overall disappointing results. After failure of first-line chemotherapy, the results of second-line therapies are distressingly poor, even with administration of high doses of cytotoxic agents such as ifosfamide.^16,17 Overall, it is well accepted that patients with unresectable sarcomas after failure of conventional chemotherapy have no therapeutic options offering proven benefit. This is a setting in which effective new therapies are desperately needed.

Ecteinascidin 743 (ET-743) is a marine-derived alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata. This compound was originally selected for further development as an antineoplastic agent on the basis of its cytotoxic potency in early preclinical studies.^18,19 The antineoplastic mechanism of action of ET-743 is not fully understood. ET-743 contains three tetrahydroisoquinoline subunits and a carbinolamine functional group; the acid-catalyzed dehydration of this functional group generates a reactive iminium intermediate that forms a covalent adduct with the N2 amino group of a guanine DNA residue.^20-22 The reaction of ET-743 with DNA induces a bend in the DNA helix towards the major groove, which is a unique feature of ET-743 among DNA-interactive agents that occupy the minor groove.²³ ET-743 has been found to interact with the transcription-coupled nucleotide excision repair machinery to induce lethal DNA strand breaks.²⁴ In addition, concentrations of ET-743, which can be achieved clinically, can block the transcription of genes that are regulated by minor-groove–interacting transcriptional factors, such as neclear factor-Y (NF-Y).^25,26 NF-Y is a critical regulator of many cell-cycle genes, including cyclin B1 and cyclin B2, which are required for transit through G2/M.²⁷ Consistent with these observations, ET-743 retards progression through the S phase of the cell cycle, eventually resulting in a G2/M block.^19,28 NF-Y also regulates the transcription of genes involved in the development of drug resistance, such as MDR1. It has been demonstrated in vitro that ET-743 abrogates transcriptional activation of the MDR1 gene induced by a variety of stimuli,²⁶ while leaving constitutive gene expression relatively unaffected.

ET-743 has exhibited antineoplastic activity in different doxorubicin- and cisplatin-resistant preclinical models.^29-31 In the phase I clinical testing of ET-743, tumor responses were observed in patients with a wide variety of malignancies, including leiomyosarcoma, liposarcoma, osteosarcoma, melanoma, and mesothelioma, as well as carcinomas of the breast and ovary.^32-35 The demonstration of several objective responses from these early clinical trials in heavily pretreated patients with mesenchymal tumors, as well as the significant need for effective new therapy in this clinical setting, encouraged further clinical development of ET-743 in this patient population.

The primary objective of this phase II multicenter study was to assess the clinical activity of ET-743 in patients with surgically incurable advanced or metastatic soft tissue sarcoma with disease progression despite one or two prior chemotherapy regimens for advanced disease. Secondary objectives of the study were to characterize the toxicity profile and pharmacokinetic behavior of ET-743 in this patient population.

	PATIENTS AND METHODS

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Patient Selection
Patients with histologically confirmed recurrent or metastatic soft tissue sarcoma with disease progression despite prior chemotherapy with two or fewer prior regimens for advanced disease were eligible for the trial. 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.

The interval between major surgery or any other prior anticancer treatment (chemotherapy, radiotherapy, or immunotherapy) and study entry was 4 weeks or longer ( 6 weeks if prior chemotherapy had included nitrosoureas or mitomycin). Any toxicities from prior therapies must have resolved before study registration (except for peripheral neuropathy < grade 2 by the National Cancer Institute Common Toxicity Criteria [NCI-CTC]³⁶). Other eligibility criteria included the following: Eastern Cooperative Oncology Group performance status of 1, presence of at least one bidimensionally measurable lesion (computed tomography scan lesion 20 mm in at least one diameter or clinically measurable lesion 20 x 20 mm) located in a nonirradiated area, age 18 years old, minimum life expectancy of 3 months, adequate bone marrow reserve (neutrophil count 1.5 x 10⁹/L and platelet count 100 x 10⁹/L), and normal renal and hepatic function (creatinine 132 µmol/L [1.5 mg/dL] or creatinine clearance 40 mL/min and serum bilirubin and alkaline phosphatase the upper limit of normal, AST and ALT < 2.5 times the upper limit of normal, and albumin > 25 g/L). Patients were ineligible for the study if they had a history of another neoplastic disease (except prior basal cell carcinoma or cervical carcinoma-in-situ that had been previously treated adequately), any other serious uncontrolled medical or psychiatric conditions, or brain or leptomeningeal tumor involvement. Women of childbearing potential could not be pregnant or lactating, and both fertile males and females were to use medically approved contraception, per standard clinical research practice. Any patient with compromised ability to give informed consent or to complete the study as judged by the investigator was also excluded. All patients were required to have an indwelling central venous access device (eg, portacath) in place for drug administration. A signed written informed consent was obtained from each patient before registration.

Study Design
This phase II clinical trial was conducted at three institutions in the United States. The study protocol was reviewed and approved by the appropriate Scientific Review Committees and Institutional Review Boards at each site. The primary end point of the study was to determine the response rate of ET-743 in previously treated patients with advanced soft tissue sarcomas. Secondary end points were to further characterize the toxicity profile and pharmacokinetic behavior of ET-743 in this patient population.

Prestudy assessments were to be performed within 14 days before initiating therapy and included the following: medical history and physical examination, complete blood count with differential counts, serum chemistry profile (alkaline phosphatase, AST, ALT, lactate dehydrogenase, bilirubin, creatinine, serum electrolytes and calcium, total protein, and creatine kinase), urinalysis, ECG, and chest x-ray. Baseline assessment of all measurable sites of disease using an appropriate radiologic technique was performed within 4 weeks of study entry.

ET-743 was to be administered on an outpatient basis every 3 weeks as a 24-hour continuous intravenous (IV) infusion at an initial dose of 1,500 µg/m². The clinical dosage form of ET-743 was supplied by PharmaMar, S.A. (Madrid, Spain) as a sterile lyophilized powder in glass vials containing 250 µg of the drug, 0.25 mmol of sodium phosphate, and 250 mg of mannitol. The vials were stored frozen at –10 to –20°C, protected from light, and reconstituted by adding 5 mL of sterile water for injection, US Pharmacopeia, which afforded a clear solution buffered to pH 4. CADD programmable ambulatory infusion pumps (SIMS Deltec, St. Paul, MN) were used to deliver the drug through a central venous catheter. The required volume of reconstituted drug solution (50 µg/mL) was loaded into a 100-mL medication cassette reservoir and further diluted with normal saline for injection, US Pharmacopeia, such that the desired daily dose was delivered in a volume of 96 mL.

History and physical examinations as well as repeat evaluation of all baseline laboratory parameters were performed before each cycle of therapy to ensure that the patient had recovered sufficiently to allow repeat administration of ET-743. Toxicity was evaluated in each cycle and graded according to the NCI-CTC version 2.0.³⁶ Complete blood counts with differential counts, liver function tests, and creatine kinase were performed weekly throughout the study. Liver function tests were also performed on day 4 of each cycle.

Neither granulocyte colony-stimulating factor nor granulocyte-macrophage colony-stimulating factor was permitted as hematopoietic supportive care in the initial cycle of therapy. Although the first six patients on study did not receive routine premedication with dexamethasone as a prophylactic antiemetic, the study was amended to allow this agent to be used as a premedication after data showed that there was no significant impact of this corticosteroid on ET-743 metabolism. Thereafter, the majority of patients received an antiemetic regimen that included dexamethasone (10 mg via either oral or IV route) and ondansetron (24 mg via either oral or IV route). Each cycle was to be administered at 21-day intervals if the patient had completely recovered to baseline values from hematologic and liver toxicities and to NCI-CTC grade 1 or less from nonhematologic toxicity other than hepatic. Whenever these conditions were not satisfied at day 21, a maximum delay of 2 weeks in the treatment cycle was permitted to allow for adequate recovery. If toxicities had not recovered by day 35 of the treatment cycle, the patient was withdrawn from the study. Dose adjustments were based on the most severe toxicity noted in the previous cycle. The dose of ET-743 was reduced to 1,200 µg/m² if any of the following occurred: grade 4 neutropenia lasting 5 days or associated with fever or infection, grade 4 thrombocytopenia, grade 1 elevation of alkaline phosphatase or bilirubin, grade 2 cardiac or neurologic toxicity, and/or other grade 3 to 4 nonhematologic toxicities. Any patient experiencing grade 3 or greater cardiac or neurologic toxicity would be withdrawn from the study. Because ET-743 was known to induce transient and reversible increases of serum transaminase levels with no cumulative effect and no clinical repercussions,^32,35 no dose reduction was required if grade 3 to 4 AST or ALT elevations occurred as long as these reverted to baseline values (grade 1) by day 21 of each cycle. If grade 3 to 4 transaminitis resolved with delayed kinetics (ie, resolution between cycle day 22 to 35), the patient could continue treatment with a reduction in the dose of ET-743 to 1,200 µg/m². If any hepatic grade 3 to 4 toxicity did not resolve to baseline values by day 35, the patient was withdrawn from study. If any reason for dose reduction noted above recurred in a patient whose dose had previously been reduced to 1,200 µg/m², subsequent cycles of ET-743 were to be administered at 1,000 µg/m². Any patient requiring further dose reductions below 1,000 µg/m² was withdrawn from study. Patients were also removed from study for any of the following reasons: the development of any adverse effect judged by the investigator to be detrimental to the patient's health, patient noncompliance, or patient decision to discontinue treatment.

Patients were evaluated for tumor response by conventional methods, according to the standard WHO criteria,³⁷ at least after every two cycles of therapy until disease progression. Treatment with ET-743 was continued until disease progression unless the patient met withdrawal criteria. A complete response was defined as the disappearance of all measurable and assessable evidence of disease. A partial response was defined as a minimum reduction of at least 50% of the sum of the products of the longest perpendicular diameters of all measurable lesions with no development of any new lesion. A minor response was defined as a reduction of between 25% to 49% of the sum of the products of the longest perpendicular diameters of all measurable lesions without appearance of any new lesion. When multiple lesions were present, up to six measurable target lesions representative of all organs involved were selected before initiating therapy to define response. A decrease in tumor burden of less than 25% or an increase that did not exceed 25% was considered stable disease. Progressive disease was indicated by a more than 25% increase in the dimensions of at least one measurable lesion over the smallest measurements observed or the appearance of any new lesion. Partial or complete responses were to be confirmed by repeating the appropriate imaging procedures 4 weeks after the objective response was first documented.

Pharmacokinetics
The plasma pharmacokinetics of ET-743 were characterized during the first cycle of therapy in a subset of patients using a limited sampling schedule. Blood specimens (7 mL) were drawn from an arm vein into a Vacutainer Brand tube with freeze-dried sodium heparin anticoagulant (Becton Dickinson, Franklin Lakes, NJ) at the following times relative to the start of the drug infusion: 0, 2, 23.5, 24.5, 25, 48, and 72 to 96 hours. Sample tubes were mixed by inversion and placed on wet ice until centrifuged (1,800 x g, 10 minutes, 4°C) within 15 minutes, on which the plasma was transferred into a polypropylene cryovial and stored at –70°C until assayed. The beginning and ending times of the drug infusion and sample collection intervals were monitored with a digital timer and recorded to the nearest second.

A validated analytic method based on isocratic reversed-phase high-performance liquid chromatography with electrospray ionization mass spectrometric detection was used to measure the concentration of ET-743 in plasma, as previously described.³⁵ Each study sample was independently assayed in duplicate, on different days, together with a series of standard solutions of ET-743 in plasma at concentrations ranging from 50 to 1,000 pg/mL. Standard curves were analyzed by linear regression using a weighting factor of 1/yr_obs. Values of the parameters describing the best-fit line were used to calculate the ET-743 concentration in study samples. Specimens with an estimated concentration above the upper limit of the standard curve were reassayed in duplicate on appropriate dilution with drug-free plasma. Study samples were also reassayed in cases where the two initial determinations differed from their average by more than 20%. During its application to the present study, the between-day accuracy and precision of the assay were assessed by analyzing the interpolated drug concentrations from 21 standard curves run over a 40-week period. Grand mean ± standard deviation values of the between-day accuracy and precision were 101.5% ± 9.1% (range, 91.5% to 112.9%) and 9.9% ± 3.2% (range, 4.8% to 12.9%), respectively.

Actual sample times were calculated from the beginning of the first infusion of drug to the midpoint of each sample collection interval. Individual patient plasma concentration versus time data were analyzed by noncompartmental methods using routines supplied in the WINNonlin Version 1.1 software package (Scientific Consulting, Apex, NC). Area under the curve (AUC) of plasma profiles from time zero to infinity was estimated using the logarithmic-linear trapezoidal algorithm to the last data point, with extrapolation to time infinity using the estimated value of the slope of the terminal logarithmic-linear disposition phase. Total plasma clearance (Cl) was calculated as the dose divided by AUC. Mean values of the pharmacokinetic variables were calculated as the geometric mean of the individual patient values.³⁸ Standard deviations for the geometric mean values were estimated using the jacknife method.³⁹ Parametric statistical tests using log-transformed values of the maximum plasma concentration (C_max), AUC, or CL of ET-743 were performed to identify differences between subgroups of patients categorized according to demographic characteristics, toxicity grade, or response.⁴⁰ P < .05 (two-tailed) was considered to be significantly different.

Statistical Methods
A two-stage Simon design,⁴¹ which allows for accrual termination if extreme results are obtained, was used to calculate sample size; this was based on a null hypothesis, where the probability of objective response (complete and partial response) was P₀ 0.05, and an alternative hypothesis, where the probability of objective response was P₁ 0.15, assuming a significance level of P = .05 and a power of 1-ß = 0.8. The total target population was 36 patients. If no objective response was observed in the initial 20 patients, further accrual to the study was to be halted.

Descriptive statistics were used to characterize response and toxicity rates. The response rate was estimated as the proportion of patients who achieved a complete or partial response among all patients registered on the study who received at least one dose of study drug. Two-stage conditional exact binomial 95% CIs⁴² were used to describe the distribution of the response rate.

Duration of response, time to disease progression (TTP), and overall survival (OS) were estimated according to the Kaplan-Meier product-limit method. The duration of response was measured from the date that the response was first recorded to the date of disease progression. TTP was defined as the time elapsed from the date of registration to the date of the first documented evidence of progressive disease. Patients who died from sarcoma-unrelated causes before disease progression were considered censored in the analysis of TTP. OS was calculated from the time of registration to the date of death from any cause.

	RESULTS

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Patient Characteristics
From September 1999 through September 2000, 36 patients were treated on study. All patients received at least one dose of ET-743 treatment and have been included in the analysis. Patient characteristics are listed in Table 1. The median age of the study population was 48 years (range, 19 to 68 years), and the median Eastern Cooperative Oncology Group performance status was 0. The most frequent histologies were leiomyosarcoma, liposarcoma, and synovial cell sarcoma; the predominant site of metastatic disease was the lung. The majority of patients had bulky disease (77%), which was defined as having at least one lesion more than 5 cm in longest diameter. Sixty percent of the patient population had received two prior chemotherapy regimens, and a similar proportion of patients had received prior radiotherapy. All patients had been previously treated with anthracyclines, and 80% had also received prior ifosfamide therapy. Progressive disease was documented in all patients before study entry.

At the time of this analysis, all patients have come off study. The reasons for removal from study included disease progression in 31 patients, hematologic toxicity in one patient, elective surgery in one patient, patient withdrawal in one patient, and the development of a second malignancy (acute myelocytic leukemia, likely associated with prior anthracycline treatment) in one patient. In addition, one patient came off study 8 months after achieving a complete response having received 16 cycles of therapy. Seven patients (19% of study population) received more than six cycles of ET-743 on protocol.

Response Rate and Survival
Among the 36 patients who received at least one dose of the study drug, there were three major objective responses, including one complete response and two partial responses (objective response rate, 8%; 95% CI, 2% to 23%). Major responses occurred in patients with high-grade liposarcoma (one patient with myxoid/round-cell liposarcoma and one with dedifferentiated liposarcoma arising from prior well-differentiated liposarcoma) and leiomyosarcoma (one patient). Of note, one of the patients with a mixoid/round-cell liposarcoma and liver metastasis came off study 8 months after achieving a complete response having received 16 cycles of study drug. She eventually progressed 1 year after treatment discontinuation and 20 months after the complete response documentation and was then re-treated with ET-743 by a 3-hour infusion schedule on compassionate use with stabilization of her recurrent massive disease for 5 months. In addition, two good minor responses were observed in a patient with myxoid/round-cell liposarcoma (47% tumor reduction) and a patient with fibrosarcoma (43% tumor reduction). Importantly, all patients with major responses to therapy had received prior doxorubicin and ifosfamide chemotherapy and were documented to be anthracycline-resistant. Furthermore, each of these responding patients also exhibited bulky disease (> 5 cm) and a short progression-free interval of 2 to 3 months before study entry. Tumor shrinkage was observed in lung, mesenteric, retroperitoneal, and hepatic metastases. Responses evolved over several cycles of treatment (six to eight cycles) from stable disease or minor responses. The median duration of response was 9 months (range, 4 to 20 months). Tumor responses according to histologic subtype are listed in Table 2.

View larger version (14K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curve for time to progression of sarcoma patients, after failure of prior chemotherapy, treated with ecteinascidin 743 (——) with 95% CI ( · · · ).

View larger version (14K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curve for overall survival of sarcoma patients, after failure of prior chemotherapy, treated with ecteinascidin 743 (– –) with 95% CI ( · · · ).

Complete sets of plasma concentration-time data for ET-743 were obtained from 28 of the 35 patients entered onto the study. The mean AUC of ET-743 was 40.0 ± 15.6 ng · h/mL (range, 22.7 to 114.3 ng · h/mL), and the mean Cl was 35.6 ± 16.2 L/h/m². The mean value of the observed C_max of the drug was 1.04 ± 0.48 ng/mL. The AUC was used to evaluate associations between ET-743 pharmacokinetics and demographic characteristics of the patients or pharmacodynamic effects because it seemed that the AUC (coefficient of variation [CV], 39.0%) was estimated with greater precision than the C_max (CV, 47.1%), as indicated by the values of their CVs. There were no statistically significant differences in the mean AUC for patients when grouped according to sex, age ( 40 years v > 40 years), or performance status (0 v 1). Neutropenia was the only toxicity for which there was a significant difference in the AUC among patients experiencing severe toxicity compared with all other patients. Specifically, the mean AUC in patients with grade 3 to 4 neutropenia was 57.1 ± 25.3 ng · h/mL (n = 7), and it was 35.5 ± 10.5 ng · h/mL (n = 21) in patients with grade 0 to 2 toxicity (P = .032). The mean AUC in the four patients who experienced grade 2 fatigue (57.6 ± 33.0 ng · h/mL) was much larger than in patients with grade 0 (36.6 ± 13.0 ng · h/mL, n = 17) and grade 1 fatigue (40.1 ± 11.6 ng · h/mL, n = 7); however, the difference was not statistically significant (P = .24). Furthermore, the mean AUC during cycle 1 was not significantly greater (P = .79) in the 10 patients requiring dose reduction or delay in treatment on the basis of serum transaminase levels that failed to decline to baseline levels by day 21 (40.1 ± 10.1 ng · h/mL) compared with patients who fully recovered from hepatotoxicity within this time frame (38.7 ± 15.6 ng · h/mL). However, the patient with the greatest C_max (3.9 ng/mL) and AUC (114.3 ng · h/mL) observed in this study was also the only patient exhibiting a grade 2 elevation in alkaline phosphatase during cycle 1; although, surprisingly, this patient developed only grade 1 transaminitis. This patient also experienced severe hematologic toxicity, characterized by grade 4 neutropenia, a grade 3 decrease in WBC, and grade 2 anemia. There was no discernable difference in either the AUC or C_max of the drug in the seven patients who showed evidence of tumor reduction compared with the patients whose tumors continually progressed during therapy.

	DISCUSSION

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Unresectable advanced or metastatic soft tissue sarcoma represents a life-threatening disease for which new and effective treatments are urgently required. Despite relatively low response rates and significant regimen-related toxicities, the mainstay of current chemotherapy remains doxorubicin and ifosfamide, administered either as single agents or in combination. For patients whose disease progresses despite prior doxorubicin or ifosfamide therapy, therapeutic options are, unfortunately, limited. The present multi-institutional phase II study demonstrates that a new marine-derived antineoplastic agent, ET-743, is active in a subset of previously treated patients with chemotherapy-resistant soft tissue sarcomas, with an overall clinical benefit rate of 14% and an acceptable toxicity profile. Importantly, the OS rate in this single-arm treatment study was 74% at 6 months, which compares favorably to any historical measure of survival for patients with progressive sarcoma after failure of prior chemotherapy. This degree of objective activity, although modest and requiring larger trials for confirmation, is important because this is a patient population in which essentially no new drug has shown to have reproducible activity since the introduction of ifosfamide into practice in the early 1980s. Of note, all three major objective responses in our study were observed in patients with anthracycline-resistant disease that had also failed to respond to prior ifosfamide therapy, and these major responses have proven durable for up to 20 months.

Our results are in concordance with those described in preliminary reports from two other phase II trials of ET-743 that are ongoing in Europe, with response rates ranging between 9% and 13%.^43,44 In contrast, however, ET-743 at this dose and schedule in our experience has been adequately well tolerated, as documented by the facts that only one patient came off study because of treatment-induced toxicity (slow hematologic recovery) and patients received 92% of the planned dose-intensity on average. The differences in safety and tolerability between the experience in our trial and the data from European studies are likely a result of several factors. Specifically, our study benefited from extensive analysis of the pooled database of 331 ET-743–treated patients included in different phase I and early phase II studies involving both Europe and the United States. This analysis revealed that 2% of the patients developed severe multiorgan toxicity including long-lasting pancytopenia, renal and hepatic failure, and rhabdomyolysis, which was fatal in three patients.⁴⁵ Subsequent identification of biochemical parameters that were predictive for the occurrence of severe toxicities,⁴⁵ such as increased baseline bilirubin or intercycle alkaline phosphatase elevations, led to the implementation of strict liver function test criteria in our study reported here as well as subsequent trials. Strict normalcy of hepatic function was required both for study entry and for patients to remain eligible to receive subsequent cycles of ET-743. The implementation of these rigorous monitoring and eligibility screens has greatly improved the safety and tolerability of ET-743 compared with the earliest clinical experience with this agent. This is supported by the finding that all toxicities in our study were reversible and manageable and that we encountered no life-threatening toxicities or drug-related deaths on study.

The pharmacologic Cl of ET-743 in patients with soft tissue sarcomas, 35.6 ± 16.2 L/h/m², was in close agreement with the mean value of 32.5 ± 14.0 L/h/m² for the cohort of patients evaluated at the 1,500 µg/m² dose level during the phase I study of the drug given as a 24-hour infusion.³³ Moreover, the degree of interpatient variability in the Cl (CV, 45.5%) was also similar to that observed in previous studies (CV, 43.1%). These findings support the ability of the empirically based limited sampling schedule used in this study to accurately estimate the AUC of ET-743 when given as a 24-hour IV infusion. Among the 28 patients for whom pharmacokinetic data was obtained during the first cycle of therapy, there were no significant differences between the AUC in patients grouped according to their demographic characteristics, severity of toxicity with the exception of neutropenia, or response to therapy. The AUC determined during cycle 1 was not predictive of patients who required either a dose reduction or delay in treatment with the second cycle of therapy as a result of prolonged recovery from hepatic toxicity. Consequently, it does not seem that the safety, tolerability, or effectiveness of ET-743 could be further enhanced by pharmacokinetic drug-level monitoring in individual patients with good performance status and close to normal hepatic and renal function when administered according to the dose and schedule evaluated in this study.

Dexamethasone was used as a prophylactic antiemetic in 30 of the patients evaluated in this study. Treatment with dexamethasone was typically initiated coincident with the ET-743 infusion and continued for one additional day, with the majority of patients (28 of 30 patients) receiving 10 mg daily. Metabolism by enzymes comprising the cyctochrome P4503A subfamily, which are well known to be subject to induction by dexamethasone, is believed to be an important pathway of elimination for ET-743.^35,46,47 Accordingly, the potential for decreased systemic exposure to ET-743 as a factor contributing to the effectiveness of dexamethasone to mitigate the nausea and vomiting induced by the drug was a concern. A meaningful statistical comparison to assess the influence of dexamethasone cotreatment on the AUC of ET-743 could not be performed because only four of the 28 patients for whom pharmacokinetic data was available did not receive the glucocorticoid. Nevertheless, in consideration of the similar values for the Cl of the drug determined in this study and the phase I trial of the 24-hour infusion schedule, for which the use of dexamethasone was specifically precluded, it is unlikely that the administration of dexamethasone in this manner has a clinically significant effect on the pharmacokinetics of ET-743. Therefore, it seems that the antiemetic benefit achieved through the use of dexamethasone is a pharmacodynamic effect rather than a consequence of enhanced ET-743 elimination.

Soft tissue sarcomas constitute a heterogenous group of tumors that present challenges to clinicians and scientists with regard to pathogenesis, diagnosis, and treatment. Conventional chemotherapy with doxorubicin or ifosfamide induces response rates in 20% to 30% of previously untreated patients and in 8% to 16% of pretreated patients.^11,16 Complete responses are uncommon and do not seem to translate into prolonged survival. Phase III trials have shown that combination chemotherapy may increase the response rate in this patient population,^6,48 although at the expense of a significant increase in toxicity with no benefit in survival.^4,6,48 Other therapeutic approaches, such as increasing dose-intensity, have yielded similar results in randomized studies, with modest improvements in response rates¹⁷ or progression-free survival⁴⁹ but no impact on OS. Second-line treatment for patients who experience treatment failure with doxorubicin or ifosfamide therapy is remarkable for the striking lack of active agents. In this context, a new drug such as ET-743, with the ability to induce responses in patients with bulky tumors, liver metastasis, and anthracycline-resistant disease, seems highly worthy of further evaluation. Although the incidence of major objective responses is relatively low, the clinical benefit rate, which includes minor responses, may be a more relevant assessment of the true clinical activity of this agent in sarcomas, which have traditionally presented challenges in assessment of antitumor efficacy of systemic therapies. The European Organization for Research and Treatment of Cancer (EORTC) Sarcoma Group has previously published data as well that indicate that the variables predictive of survival do not necessarily correlate with the variables that predict objective response to therapy.⁵⁰ This hypothesis is also supported by the favorable OS rate observed in our study, suggesting that ET-743 may also be able to delay progression of disease in a subset of patients without objective responses and, thus, may have an impact on improving survival as the most important end point of clinical benefit. It is also encouraging that our results are fully consistent with preliminary reports from two additional European studies using ET-743 in this patient population.^43,44

Adult soft tissue sarcomas have generally been grouped together in clinical trials because of the rarity of the distinct histologic subtypes and the difficulties in performing separate clinical trials to target specific histopathologic subtypes. However, potentially important differences in response to therapy clearly exist between histologic subsets of soft tissue sarcomas. It should be noted that two of the major responses observed in our study and one minor response (48% tumor reduction) occurred in patients with liposarcomas, two of which comprised the myxoid/round-cell subtype. This represents a response rate of 30% for the subset of 10 patients included in the study with the histologic diagnosis of liposarcoma. Consistent with the hypothesis that important differences exist between different subsets of sarcomas, the variable of liposarcoma histology was found to retain independent predictive value for response to chemotherapy in the multivariate analysis of prognostic factors performed by the European Organization for Research and Treatment of Cancer in more than 2,000 sarcoma patients treated with a variety of chemotherapy regimens.⁵⁰ The factors responsible for the increased sensitivity of this histologic subtype to cytotoxic therapy compared with other soft tissue sarcomas are presently unknown. Recent developments in the field of molecular biology and cytogenetics have greatly improved the diagnostic accuracy of soft tissue sarcomas and are beginning to provide important prognostic information in specific sarcoma subtypes. Liposarcoma represents the most common form of soft tissue sarcoma in humans.⁵¹ Several histologic subtypes of liposarcoma have been well characterized, with differentiation status of the cells being a major distinguishing feature among subtypes.⁵¹ The prognosis of liposarcoma, including risk of developing metastatic disease and likelihood of long-term survival, correlates well with the histologic subclassification. The myxoid and round-cell subtypes of liposarcoma, comprising approximately 35% of all liposarcomas, represent a histologic continuum that may be grouped together based on the presence of a characteristic reciprocal translocation between chromosomes 12 and 16.⁵¹ This t(12;16) generates a chimeric mRNA fusion transcript derived from the CHOP gene on chromosome 12 with the TLS gene on chromosome 16. This chimeric transcript may function as a transcriptional activator. It is intriguing to postulate that the particular sensitivity of the myxoid/round-cell liposarcomas may be the result of a molecular mechanism related to the DNA minor groove–binding activity of ET-743 and its interaction with such an aberrant transcriptional regulator.

Leiomyosarcoma was the predominant histologic subtype entered onto this phase II study. Leiomyosarcomas, particularly those of visceral origin metastatic to the liver, have been reported to have low response rates with chemotherapy.⁵⁰ However, one of the partial responses in the present trial was observed in a patient with hepatic metastases from leiomyosarcoma. Responses to ET-743 in patients with this histologic subtype have also been reported in European trials.^43,44 These data together indicate that the antineoplastic activity of ET-743 is not restricted to liposarcomas.

In summary, we can conclude that ET-743 represents a promising new anticancer agent with an acceptable safety and tolerability profile. These conclusions are based on several studies, including the one presented here, which documents activity in a subset of patients with soft tissue sarcomas whose tumors were progressive despite prior therapy with conventional chemotherapy. Further studies to evaluate the activity of ET-743 in sarcomas are justified based on the promising survival data as well as the documented incidence of clinically meaningful disease control and durable responses. Ongoing trials are in progress to assess shorter infusion schedules with an aim to improve patient convenience without compromising efficacy. Investigation of this agent in combination with other cytotoxic drugs is also warranted because preclinical data indicate that there are sequence-dependent synergies between ET-743 and anthracyclines, taxanes, and platinum compounds.⁵² In addition, its ability to abrogate transcriptional activation of the MDR1 gene may make this drug an efficacious adjuvant to the treatment of multidrug-resistant tumors.²⁶ Finally, given the paucity of active agents for this disease, further evaluation of this drug has been undertaken to establish its activity in earlier stages of the disease, and large-scale randomized trials are planned to define the impact of ET-743 on clinical outcomes for patients with soft tissue sarcomas for whom conventional chemotherapy has proved to be ineffective.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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. Owns stock (not including shares held through a public mutual fund): M.A. Sancho, C. Guzman, J. Jimeno, PharmaMar. Acted as a consultant within the last 2 years: R. Garcia-Carbonero, J. Manola, M.V. Seiden, R.G. Maki, G.D. Demetri, PharmaMar. Performed contract work within the last 2 years: R. Garcia-Carbonero, J. Manola, PharmaMar. Served as an officer or member of the Board of a company: J. Jimeno, PharmaMar. Received more than $2,000 a year from a company for either of the last 2 years: R. Garcia-Carbonero, J. Manola, M.V. Seiden, R.G. Maki, G.D. Demetri, PharmaMar; U. Matulonis, Amgen, GlaxoSmithKline, Ortho Biotech, Novartis.

	Acknowledgment

 
We thank M. Gallant and L. Butkiewicz for their important roles in the pharmacokinetic sample collection and quantitation during this study. We also thank A. Torre for her coordination of patient referrals and accrual.

	NOTES

 
Supported in part by a grant of the Ministerio de Educacion y Cultura, Spain (R.G.-C.), and by research support from PharmaMar, Madrid, Spain.

Preliminary results of the study were presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.

Both R.G.-C. and J.G.S. contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. CA Cancer J Clin 50:7-33, 2000[Abstract]

2. Morton DL, Antman KH, Tepper J: Soft tissue sarcomas, in Holland JF, Bast RC, Morton DL, et al (eds): Cancer Medicine (ed 4). Philadelphia, PA, Williams & Wilkins, 1997, pp 2559-2592

3. Brennan MF, Casper ES, Harrison LB. Soft tissue sarcoma, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer Principles and Practice of Oncology (ed 5). Philadelphia, PA, Lippincott, 1997, pp 1738-1788

4. Santoro A, Tursz T, Mouridsen H, et al: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: A randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 13:1537-1545, 1995[Abstract/Free Full Text]

5. Bramwell VH, Mouridsen HT, Santoro A, et al: Cyclophosphamide versus ifosfamide: Final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 23:311-321, 1987[CrossRef][Medline]

6. Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11:1269-1275, 1993[Abstract/Free Full Text]

7. Buesa JM, Mouridsen HT, Oosteron ATV, et al: High-dose DTIC in advanced soft-tissue sarcoma in the adult: A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol 2:307-309, 1991[Abstract/Free Full Text]

8. Mouridsen HT, Bastholt L, Somers R, et al: Adriamycin versus epirubicin in advanced soft tissue sarcomas: A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol 23:1477-1483, 1987[CrossRef][Medline]

9. Brenner J, Magill GB, Sordillo PP, et al: Phase II trial of cisplatin (CPDD) in previously treated patients with advanced soft tissue sarcoma. Cancer 50:2031-2033, 1982[CrossRef][Medline]

10. Goldstein D, Cheuvart B, Trump DL, et al: Phase II trial of carboplatin in soft-tissue sarcoma. Am J Clin Oncol 13:420-423, 1990[Medline]

11. Verweij J, Lee SM, Ruka W, et al: Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: A study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 18:2081-2086, 2000[Abstract/Free Full Text]

12. Casper ES, Waltzman RJ, Schwartz GK, et al: Phase II trial of paclitaxel in patients with soft-tissue sarcoma. Cancer Invest 16:442-446, 1998[Medline]

13. Bramwell VH, Eisenhauer EA, Blackstein M, et al: Phase II study of topotecan (NSC 609 699) in patients with recurrent or metastatic soft tissue sarcoma. Ann Oncol 6:847-849, 1995[Abstract/Free Full Text]

14. Fidias P, Demetri G, Harmon D: Navelbine shows activity in previously treated sarcoma patients: Phase II results from MGH/Dana-Farber/Partners Cancer Care study. Proc Am Soc Clin Oncol 17:513a, 1998 (abstr 1977)

15. Spath-Schwalbe E, Genvresse I, Koschuth A, et al: Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas. Anticancer Drugs 11:325-329, 2000[CrossRef][Medline]

16. Nielsen OS, Judson I, van Hoesel Q, et al: Effect of high-dose ifosfamide in advanced soft tissue sarcomas: A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 36:61-67, 2000

17. Van Oosterom AT, Mouridsen HT, Nielsen OS, et al: Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer 38:2397-2406, 2002

18. Rinehart K, Holt T, Fregeau N, et al: Ecteinascidins 729, 743, 745, 759A, 759B, and 770: Potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J Org Chem 55:4512-4515, 1990[CrossRef]

19. Jimeno J, Faircloth G, Cameron L, et al: Progress in the acquisition of new marine-derived anticancer compounds: Development of ecteinascidin-743 (ET-743). Drugs Future 21:1155-1165, 1996

20. Guan Y, Sakai R, Rinehart K, et al: Molecular and crystal structures of ecteinascidins: Potent antitumor compounds from the Caribbean tunicate ecteinascidia turbinata. J Biomol Struct Dyn 10:793-818, 1993[Medline]

21. Pommier Y, Kohlhagen G, Bailly C, et al: DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate ecteinascidia turbinata. Biochemistry 35:13303-13309, 1996[CrossRef][Medline]

22. Moore BM, Seaman FC, Hurley LH: NMR-based model of an ecteinascidin 743-DNA adduct. J Am Chem Soc 119:5475-5476, 1997[CrossRef]

23. Zewail-Foote M, Hurley LH: Ecteinascidin 743: A minor groove alkylator that bends DNA toward the major groove. J Med Chem 42:2493-2497, 1999[CrossRef][Medline]

24. Takebayashi Y, Pourquier P, Zimonjic DB, et al: Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 7:961-966, 2001[CrossRef][Medline]

25. Minuzzo M, Marchini S, Broggini M, et al: Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci USA 97:6780-6784, 2000[Abstract/Free Full Text]

26. Jin S, Gorfajn B, Faircloth G, et al: Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc Natl Acad Sci USA 97:6775-6779, 2000[Abstract/Free Full Text]

27. Zwicker J, Muller R: Cell-cycle regulation of gene expression by transcriptional repression. Trends Genet 13:3-6, 1997[CrossRef][Medline]

28. D'Incalci M, Erba E, Faretta M, et al: New drugs of marine origin. Ann Oncol 7:34, 1996 (suppl 1)

29. Hendriks HR, Fiebig HH, Giavazzi R, et al: High antitumour activity of ET743 against human tumour xenografts from melanoma, non-small-cell lung and ovarian cancer. Ann Oncol 10:1233-1240, 1999[Abstract/Free Full Text]

30. Valoti G, Nicoletti MI, Pellegrino A, et al: Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts. Clin Cancer Res 4:1977-1983, 1998[Abstract]

31. Izbicka E, Lawrence R, Raymond E, et al: In vitro antitumor activity of the novel marine agent, ecteinascidin-743(ET-743, NSC-648766) against human tumors explanted from patients. Ann Oncol 9:981-987, 1998[Abstract/Free Full Text]

32. Van Kesteren C, Twelves C, Bowman A, et al: Clinical pharmacology of the novel marine-derived anticancer agent ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study. Anticancer Drugs 13:381-393, 2002[CrossRef][Medline]

33. Taamma A, Misset JL, Riofrio M, et al: Phase I and pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors. J Clin Oncol 19:1256-1265, 2001[Abstract/Free Full Text]

34. Villalona-Calero MA, Eckhardt SG, Weiss G, et al: A phase I and pharmacokinetic study of ecteinascidin-743 on a daily x 5 schedule in patients with solid malignancies. Clin Cancer Res 8:75-85, 2002[Abstract/Free Full Text]

35. Ryan DP, Supko JG, Eder JP Jr, et al: Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72 hour continuous intravenous infusion in patients with solid malignancies. Clin Cancer Res 7:231-242, 2001[Abstract/Free Full Text]

36. The Cancer Therapy Evaluation Program: Common toxicity criteria manual, 8/99 update. http://ctep.info.nih.gov/CTC3/CTC-Manual.htm

37. World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication no. 48., Geneva, Switzerland, World Health Organization, 1979

38. Mizuta E, Tsubotani A: Preparation of mean drug concentration-time curves in plasma: A study on the frequency distribution of pharmacokinetic parameters. Chem Pharm Bull 33:1620-1632, 1985

39. Lam FC, Hung CT, Perrier DG: Estimation of variance for harmonic mean half-lives. J Pharm Sci 74:229-231, 1985[Medline]

40. Lacey LF, Keene ON, Pritchard JF, et al: Common noncompartmental pharmacokinetic variables: Are they normally or log-normally distributed?. J Biopharm Stat 7:171-178, 1997[Medline]

41. Simon R: Optimal two-stage designs for clinical trials. Control Clin Trials 10:1-10, 1989[Medline]

42. Atkinson EN, Brown BW: Confidence limits for probability of response in multistage phase II clinical trials. Biometrics 41:741-744, 1985[CrossRef][Medline]

43. Le Cesne A, Blay JY, Judson I, et al: ET-743 is an active drug in adult soft-tissue sarcoma (STS): A STBSG-EORTC phase II trial. Proc Am Soc Clin Oncol 20:353a, 2001 (abstr 1407)

44. Delaloge S, Yovine A, Taamma A, et al: Ecteinascidin-743: A marine-derived compound in advanced, pretreated sarcoma patients—Preliminary evidence of activity. J Clin Oncol 19:1248-1255, 2001[Abstract/Free Full Text]

45. Gómez J, López Lázaro L, Guzmán C, et al: Identification of biochemical parameters that predict the onset of severe toxicities in patients treated with ET-743. Proc Am Soc Clin Oncol 19:187a, 2000 (abstr 727)

46. Reid JM, Kuffel MJ, Ruben SL, et al: Rat and human liver cytochrome P-450 isoform metabolism of ecteinascidin 743 does not predict gender-dependent toxicity in humans. Clin Cancer Res 8:2952-2962, 2002[Abstract/Free Full Text]

47. Reid JM, Kuffel MJ, Squillace DP, et al: Characterization of the in vitro metabolism, pharmacokinetics, and biliary excretion of ecteinascidin 743 (NSC 648766) in male and female rats. Ann Oncol 9:S50, 1998 (suppl 2)

48. Antman K, Crowley J, Balcerzak S, et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 11:1276-1285, 1993[Abstract/Free Full Text]

49. Le Cesne A, Judson I, Crowther D, et al: Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. J Clin Oncol 18:2676-2684, 2000[Abstract/Free Full Text]

50. Van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al: Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: An analysis of 2,185 patients treated with anthracycline-containing first-line regimens—A European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 17:150-157, 1999[Abstract/Free Full Text]

51. Mentzel T, Fletcher CD: Lipomatous tumours of soft tissues: An update. Virchows Arch 427:353-363, 1995[Medline]

52. Takahashi N, Li WW, Banerjee D, et al: Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin Cancer Res 7:3251-3257, 2001[Abstract/Free Full Text]

Submitted February 21, 2002; accepted February 2, 2004.

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