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Journal of Clinical Oncology, Vol 22, No 5 (March 1), 2004: pp. 890-899 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.05.210 Phase II Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma PatientsFrom the Hôpital Paul Brousse; Institut Gustave Roussy, Villejuif; Cvitkovic et Associés Consultants, Kremlin Bicêtre; Centre René Huguenin, Saint Cloud; Centre Léon Bérard, Lyon, France; and PharmaMar SA Clinical Research and Development, Madrid, Spain. Address reprint requests to J.L. Misset, MD, Hôpital St Louis, Unité d'Oncologie Médicale, 1 av. Claude Vellefaux, 75010 Paris, France; e-mail: jean-louis.misset{at}sls.ap-hop-paris.fr
PURPOSE: A multicenter phase II study evaluating efficacy, safety, and pharmacokinetics of ecteinascidin-743 (ET-743) in pretreated advanced soft tissue sarcoma patients. PATIENTS AND METHODS: Patients received ET-743 1,500 µg/m2 (24-hour intravenous infusion) every 3 weeks (group 1, 26 patients with one to two prior single agents or one previous combination chemotherapy; group 2, 28 patients with three or more prior single agents or two or more previous combination chemotherapies).
RESULTS: Patients (30 women, 24 men) had a median age of 48 years (range, 22 to 71 years); 41% had leiomyosarcoma (eight of 22 of uterine origin), a median of two involved organs (range, one to four), and 93% had documented progressive disease at study entry. Patients received a median of three cycles (range, one to 20); 28% received six or more cycles. Fifty-two patients were assessable for response (WHO criteria): two partial responses, four minor responses, and nine with stable disease ( CONCLUSION: With a 4% overall response rate (95% CI, 0.5 to 12.8) and an 11% rate of third-party-verified tumor regression (overall response rate + minor response), ET-743 has a 24% 6-month disease progression control rate, confirming evidence of antitumoral activity and a manageable safety profile in patients experiencing disease progression with pretreated soft tissue sarcoma.
Soft tissue sarcomas (STSs) comprise a vast and heterogeneous group of tumors of mesenchymal origin. STSs are rare, accounting for less than 1% of adult malignancies, but have an aggressive biologic behavior and poor long-term prognosis. Despite adequate treatment and control of localized disease, approximately 40% to 50% of high-risk STS patients still develop distant metastases and die as a result of disseminated disease [1,2]. Advanced and metastatic STS is currently treated by chemotherapy, however, few cytotoxic agents have proven high clinical activity. Doxorubicin is the reference drug in first-line, single-agent treatment, with a cumulative response rate in nonpretreated patients of approximately 25%, although recent trials show lower response rates [3-5]. Ifosfamide is also widely used in first-line combination regimens with anthracyclines or as a single agent in second-line therapy after anthracycline failure; responses occur using high doses in patients who experienced disease progression after standard-dose ifosfamide [6-9]. In a recent large, multicenter, randomized European Organization for the Research and Treatment of Cancer trial, the overall response rate (ORR) for first-line, single-agent ifosfamide and doxorubicin were only 9.4% and 11%, respectively [5]. Ecteinascidin-743 (ET-743 or trabectedin; Yondelis; PharmaMar, Madrid, Spain) is a marine-derived compound isolated from the Caribbean tunicate Ecteinascidia turbinata with a novel mechanism of action and unique antitumor properties [10]. ET-743 appears to interact with DNA in a sequence-specific manner, covalently binding a guanine residue in the DNA minor groove and bending it toward the major groove, thus possibly altering DNA interactions with transcription factors and other critical nuclear proteins [11-14]. ET-743 has high preclinical activity against a number of human solid tumor cell lines and xenografts, including STSs, and shows low or no cross-resistance with several standard chemotherapeutic agents [10,15,16]. In vitro studies revealed that the administration schedule is an important parameter in ET-743 cytotoxicity, which is more active with continuous exposure. A phase I trial using a schedule of 24-hour continuous intravenous infusion (CIV) once every 3 weeks (q3w) showed that the maximum-tolerated dose was 1,800 µg/m2 and the recommended dose was 1,500 µg/m2 [17]. The principal dose-limiting toxicities observed were severe neutropenia and thrombocytopenia. Moderate or severe acute, postdosing, elevated AST and ALT was prevalent but never treatment limiting. Painful phlebitis was the most severe nonhematologic, nonhepatic toxicity; thus, administering ET-743 by central venous access is obligatory. Objective responses and clinically relevant disease stabilizations were observed among STS patients [18], prompting the initiation of this phase II trial to explore ET-743 activity in patients with pretreated STS. When this study was planned, the recommended dose of other ET-743 schedules was available but the 24-hour CIV [17] schedule was better tolerated and had a higher duration of systemic exposure compared with the 1-hour q3w and the once daily for 5 days q3w schedules, and had a higher dose-intensity compared with the 72-hour CIV q3w schedule [19-22].
Patient Population Patients were required to have advanced or metastatic, histologically proven STS; at least one unidimensionally or bidimensionally measurable lesion measured within 4 weeks of inclusion; previous treatment with at least one line of either single-agent or combination chemotherapy; documented progressive disease (PD) less than or within 6 months of last treatment; full recovery from toxic effects of prior therapy; WHO performance status (PS)  1; age at least 18 years; and adequate hepatic (normal bilirubin and alkaline phosphatase [AP]; if total AP was higher than normal, AP liver fraction and 5'-nucleotidase had to be normal or lower; AST and ALT < 2.5 x normal; albumin > 25 g/L), renal, and bone marrow function. Patients were excluded if they had received chemotherapy within 4 weeks of study entry; a history of prior malignancies (with the exception of excised cervical carcinoma-in-situ or nonmelanoma skin carcinoma); received any treatment with experimental drugs in the 30 days before study screening; brain or leptomeningeal involvement; more than 50% metastatic liver involvement; another serious medical condition; or were pregnant, breast-feeding, or not using adequate contraception. The protocol was approved by a French national ethics committee and written informed consent was obtained from all patients.
Study Design Prestudy treatment evaluation included complete medical history, physical examination, and radiologic evaluation of all measurable or assessable sites. Complete differential blood cell counts and chemistry parameters were measured at baseline and repeated weekly. Liver function tests also were performed on day 4 of each cycle. All adverse events were graded using the National Cancer Institute Common Toxicity Criteria, version 2, at each cycle. Progression-free survival (PFS) was defined as the time from initiation of therapy to the first documentation of disease progression, last contact, or death. Overall survival (OS) was defined as the time between the first study treatment and death or last contact. Patients were assessable for efficacy if they had at least one tumor assessment after receiving at least two treatment cycles or if they experienced early PD or early treatment withdrawal because of toxicity before tumor assessment. Tumor evaluation was carried out every two cycles according to standard WHO criteria [23], and responses were confirmed within 4 weeks. After treatment discontinuation, patients without PD were observed with the appropriate radiologic method every 3 months until progression was reported. Evidence of PD at study entry, partial responses (PRs), minor responses (MRs), and prolonged stable disease (SD) were reviewed by an expert committee including two independent radiologists.
Treatment was administered every 3 weeks, unless there was insufficient hematologic recovery, in which case treatment was delayed for up to 2 weeks until recovery (neutrophil count
Pharmacokinetics
Statistical Methods
Patient Characteristics Fifty-four patients (30 women, 24 men) were enrolled and treated in four French centers between February 3, 1999, and January 26, 2001 (group 1, n = 26; group 2, n = 28). Patient characteristics are summarized in Table 1 and were generally similar between the two groups. The median age was 48 years (range, 22 to 71 years). All patients were in good general condition (100% with PS 0 or 1), although significantly more patients in group 2 (71%) than group 1 (31%) had PS 1 (P = .003). A wide variety of primary tumor locations was observed (Table 1). The most common tumor type in both groups was leiomyosarcoma (22 patients; 41%), eight of which were of uterine origin. Nineteen percent of patients in group 1 had liposarcomas, 11% of patients in group 2 had fibrosarcomas, and 7% presented with gastrointestinal stromal tumors, which are well recognized as being refractory to chemotherapy. All patients had metastatic disease with a median of two involved sites (range, one to four sites), the most common sites being lung or pleura (69%), soft tissue (50%, including the primary site of disease), and liver (30%). Thirty percent of patients had bulky disease (at least one lesion  10 cm diameter). The median time between sarcoma diagnosis and ET-743 treatment was 25.1 months (range, 4 to 182.3 months); 20% of patients had less than 1 year of disease evolution, related to poor prognosis [27]; 93% of patients had PD verified by a third party, including 66% of patients in whom progression was observed within 3 months of the last chemotherapy administration (for 76% of these, the last line of treatment included anthracyclines and/or ifosfamide).
All patients had undergone surgery for the primary tumor and/or metastases. All patients in group 1 had received one prior chemotherapy regimen, whereas patients in group 2 had received a median of two prior chemotherapy regimens (range, two to six regimens; Table 2). Most patients (87%) received at least one palliative chemotherapy regimen and 83% had prior anthracycline and ifosfamide combinations. Forty-eight percent of patients were clinically resistant to anthracyclines (defined as PD within 6 months of completion of adjuvant therapy or during or within 3 months of completion of therapy for metastatic disease). Twenty-two patients in group 1 had received both anthracyclines and ifosfamide (10 were resistant to both; Table 3). In group 2, 27 patients had received both anthracyclines and ifosfamide, with 11 patients resistant to both. Globally, 39% of patients were resistant to both anthracyclines and ifosfamide. In addition, 23% of ifosfamide-resistant patients were unable to receive additional clinically relevant doses of anthracyclines because of the previous cumulative dose. There was a high incidence (26%) of grade 1 to 2 anemia at baseline but few other biologic abnormalities.
Efficacy All patients were assessable for efficacy. Tumor response was not evaluated in two patients (Table 4). One patient (group 1) died during the second treatment cycle as a result of toxicity (febrile neutropenia, renal failure, and rhabdomyolysis) and another patient (group 2) discontinued treatment after experiencing hematologic toxicity in cycle 1. Two PRs (3.7%; 95% CI, 0.5 to 12.8) were seen (6.9 and 17.4 months, respectively), four patients (7.4%) had MRs (median, 7.1 months; range, 3.4 to 19.7 months; Table 5), nine patients (17%) had SD for 6 months (median, 12.75 months; range, 6.39 to 30.62 months), and 28 patients (51.9%) showed PD. Two of the four MRs and both PRs lasted more than 6 months. Four of the patients with tumor shrinkage had leiomyosarcomas (three of which were uterine), one patient had a uterine endometrial stromal sarcoma, and one patient had a head and neck fibrosarcoma (Table 5). All received between five and 20 cycles of study treatment; response duration was 3.4, 4.1, 6.9, 10.1, 17.4, and 19.7 months, respectively. Five of the six responding patients had received prior treatment with both anthracyclines and ifosfamide, four of whom were resistant to both agents. Two patients with SD experienced clinically relevant improvement of dyspnea and one patient with PR experienced an improvement in abdominal pain, which allowed the patient to discontinue taking strong opioids. For three patients with liver, lung, and soft tissue metastases, the therapeutic impact of ET-743 permitted salvage surgery attempts. The patients were rendered tumor free and remained progression free for 6.7, 17.9, and 19.7 months, respectively.
Time-related parameters were updated until May 31, 2002. Median follow-up was 26.0 months (range, 15.3 to 38.9 months). Median PFS in all patients was 1.9 months (range, 0.69 to 30.62 months); 38.8% and 24.1% of patients were progression free at 3 and 6 months, respectively (Fig 1). Median PFS was similar in the two groups (group 1, 1.76 months; group 2, 1.90 months), as was the number of patients who were progression free at 6 months: six patients in group 1 (23.1%) and seven patients in group 2 (25%). Median OS was 12.8 months (range, 0.69 to 33.77 months). Median OS was different in the two groups (group 1: 13.72 months; group 2: 7.97 months) but 16 patients (30%; group 1, 42%; group 2, 18%) were still alive at 2 years, all with PD at the cutoff date.
PFS ratio is increasingly used to assess therapeutic effect in borderline palliative situations [28]. PFS after previous treatment was reviewed by a third party from all clinical and radiologic evidence available, as was PFS for patients receiving study treatment. PFS for patients receiving ET-743 was compared with PFS for patients receiving the previous therapy, and data from the 15 patients with tumor shrinkage and/or PFS 6 months are shown in Figure 2. In the entire population, 15 patients had a PFS ratio more than 1, including 10 who were resistant to anthracyclines (data not shown). Most interestingly, nine (69%) and seven (54%) of 13 patients with PFS 6 months had PFS ratios more than 1 and more than 2, respectively, supporting the relevance of PFS 6 months.
Safety All patients were assessed for safety. A total of 226 cycles (group 1, 98 cycles; group 2, 128 cycles) were administered, with a median of three cycles per patient (range, one to 20 cycles). Fifteen (28%) patients received at least six cycles. Extent of treatment exposure and administration were similar in the two groups. A total of 148 cycles (65%) were given at the recommended dose of 1,500 µg/m2. Median relative dose-intensity was 86% in the whole population, and was 75% in patients receiving three or more cycles. Cycle delays were similar in the two groups, with 67% of patients experiencing at least one cycle delay (> 3 days); the median delay length was 7 days. Most cycle delays and dose reductions (70%) were due to hematotoxicity. Anemia and thrombocytopenia reached grade 3 to 4 in 22% and 18% of patients, respectively. Grade 3 to 4 neutropenia was more frequent (61% of patients, 43% of cycles), lasting a median of 8 days (range, 1 to 32 days), but was infrequently complicated by fever or infection (7% of patients, 1.8% of cycles; Table 6).
Four patients (7.4%) discontinued the study because of treatment-related adverse events, including two treatment-related deaths. Two major protocol violations contributed to these deaths, both after cycle 2. In one patient, dose was not reduced after an AP increase during cycle 1, which was shown to be correlated with severe toxicity and morbidity [24]. This patient was hospitalized as a result of febrile neutropenia and acute renal failure concomitant with rhabdomyolysis (creatine phosphokinase, 49,000 U/L). The patient refused dialysis and died shortly thereafter. The other patient had a 20-year history of alcoholic cirrhosis that had been asymptomatic for many years before study entry; the patient also had known esophageal varices. No biochemical abnormalities were present at baseline. During the first cycle of treatment (1,500 µg/m2), he experienced febrile neutropenia and the dose was reduced to 1,200 µg/m2. After the second cycle, he had febrile neutropenia, diffuse muscle pain (creatine phosphokinase, 8,000 U/L), and renal failure. Despite improved hematologic and biochemistry parameters, the patient experienced gastrointestinal hemorrhage and hepatic encephalopathy, and died. Retrospectively, this compensated chronic liver illness was assessed as a major exclusion criteria violation (existing serious medical condition) because it was clearly decompensated by the study treatment. Seventy-two percent of patients discontinued treatment because of PD. Four patients in group 1 and three patients in group 2 experienced a total of 10 treatment-related serious adverse events, five of which involved febrile neutropenia, and three of which were grade 3 to 4 emesis. One episode of grade 4 thrombocytopenia and one episode of grade 3 anemia occurred. There was no evidence of any cumulative toxicities. Mucositis (grades 1 and 2) was limited to 9% of patients. Other toxicities experienced during treatment are listed in Table 6. The most common toxicities were hematologic and hepatic enzyme abnormalities. Extent of toxicity was similar in the two groups analyzed. Nausea and vomiting were prevalent in both groups but were generally mild. Almost all patients experienced abnormalities in AST and ALT (reaching grade 3 to 4 in approximately 50% of patients), which were shown to be reversible in all patients and were almost never dose limiting (1.3% of dose reductions and delays). Asthenia also was prevalent and was grade 3 to 4 in 15% of patients. Alopecia was rare (two patients, grade 1), and neither cardiotoxicity nor neurotoxicity was reported. Although hematologic growth factors were not used in the study, eight patients required transfusions of RBCs, two of whom also required platelet transfusions.
This study examined the activity and safety of ET-743, a new agent that previously has shown activity in heavily pretreated STS patients [18]. Given the prevalent use of anthracyclines in adjuvant and first-line treatment in this population, the potential for additional use of these agents is precluded by the high risk of congestive heart failure. Ifosfamide is currently the treatment of choice for patients who experience treatment failure with anthracyclines and for patients who have received the maximum-tolerated dose of anthracycline. Response rates reported with second-line ifosfamide vary quite widely (6% to 39%) [6-9,29] probably because of differences in assessment guidelines and verification methodology, as well as schedules and doses used. In a recently published study of two different ifosfamide schedules (5 g/m2/24 hours CIV and 3 g/m2/d for 3 days), there were no significant differences between the schedules when used as second-line treatment: the ORR was 6% and 8%, and PFS at 6 months was 10% and 20%, respectively [29]. This study had external peer review of response, which could explain the difference in ORR compared with previously reported studies. Most of the newly available cytotoxics have been tested both in untreated and pretreated patients with advanced STS with disappointing results. Gemcitabine yields an ORR of 3% to 18%, with 11% to 15% of patients progression free at 6 months [30-32], whereas no objective responses have been observed in first-line treatment with docetaxel [4]. Even if combination chemotherapy has failed to demonstrate statistical superiority against doxorubicin in first-line treatment, most sarcoma patients receive both doxorubicin and ifosfamide as adjuvant or first-line chemotherapy for advanced disease, as was reflected in our cohort of patients (83% of patients had received combined ifosfamide and doxorubicin). Indeed, no reliable options currently exist for STS patients who have progressed after treatment with anthracyclines and ifosfamide. Novel agents need to be investigated for activity against STS because it is unlikely that higher response rates, or PFS and survival changes, will be obtained by modifying the schedules and/or doses of doxorubicin and ifosfamide. Although the 54 treated patients were analyzed in two predefined groups on the basis of the extent of their pretreatment, few differences were found between these two groups. Two PRs (lasting 6.9 and 17.4 months, respectively) and four clinically relevant MRs were assessed (all were verified by a third party). Of particular interest is the fact that 24% of patients with proven PD at study entry were progression free at 6 months. Even if not yet prospectively validated, the rate of disease control (PR + MR + SD) at 3 to 6 months seems to be an interesting alternative end point to explore in this population of patients. The European Organization for the Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group recently published a retrospective analysis of 1,154 patients, which showed that being progression free at 3 or 6 months correlates with survival, even in the absence of objective response [33]. They also showed that the rate of PR or SD in patients after first-line chemotherapy with anthracyclines and the rate of patients who are alive at 5 years are similar [34]. This should be interpreted with caution when testing new agents, and the PD before study entry should be clearly demonstrated to avoid a false impression of activity in patients with spontaneously slow-growing tumors. This does not seem to be the case for our cohort of patients, 93% of whom had clear PD at study entry, including all patients without PD at 6 months. Median PFS in the entire treated population was 1.9 months (range, 0.69 to 30.62 months), and median PFS of patients with PR or MR was 8.5 months (range, 3.4 to 19.7 months). Although disease control (PR + MR + SD) was not a main end point of this trial at the time of its conception, a rate of disease control of 38.8% at 3 months and 24.1% at 6 months can be considered as strong ancillary evidence of the antitumoral effect of ET-743 in this patient cohort. This is even more evident if we consider that many patients (54%) without PD at 6 months had a PFS while receiving ET-743 that was at least twice the length of the PFS while receiving previous therapy, supporting the clinical value of PFS more than 6 months. Furthermore, responses were observed in multiple disease sites, including the liver, soft tissue, and lung. It is notable that four of the six patients with objective tumor shrinkage were resistant to both anthracyclines and ifosfamide. These results should be considered in the context of a population with a high incidence of adverse prognostic factors for response and/or PFS and OS (rate of leiomyosarcoma, retroperitoneal or visceral origin [27], previous exposure, burden of disease, resistance). Our results compare favorably with those obtained by other investigators in the same indication [35,36].
It is notable that in most of the published advanced STS studies, including those with doxorubicin and ifosfamide, no external review of responses and/or PFS was performed. The external review we performed may partially explain the low ORR rate. We consider that the rate of treatment-refractory patients with objective tumor shrinkage and the 24% of patients with disease control The two ET-743–related deaths are of concern. Both patients developed acute renal failure with febrile neutropenia and rhabdomyolysis; however, both patients had at least one major protocol violation that could have led to the fatal outcome. This highlights the relevance of adhering fully to the protocol and amendments during adjustment recommendations, given that nonreduction of dose after AP elevations is known to induce severe toxicity [24], and known liver disease must preclude treatment with drugs with known liver metabolism and toxicity [19]. Otherwise, the toxicities encountered in this study were manageable; hematotoxicity was the most frequently occurring severe toxicity. Elevated AST and ALT, as previously described, was transient, and led to only two dose reductions. Other toxicities were mild and usually of short or transient duration. The low rate of alopecia (4%) and the absence of either cardiotoxicity or neurotoxicity are of note. Furthermore, toxicities were not notably different between the two patient groups, showing that even heavily pretreated patients tolerate this regimen well when guidelines for patient selection and dose adjustment are respected [37]. Other studies with new administration schedules as a single agent and in combination, including this and other indications, are being explored [38,39]. Early promising results were observed with a 3-hour q3w schedule in soft tissue sarcoma (disease control at 3 months, 24% to 51% of patients; disease control at 6 months, 21%) [40,41], small round cell sarcoma [42], and ovarian cancer (response rate 28%) [43], and with the 24-hour CIV schedule in breast cancer (response rate of 13% in heavily pretreated patients) [44]. The 3-hour q3w schedule was also shown to be safe in a pediatric population bearing solid tumors [45]. Even if the 24-hour CIV schedule allows delivery of a higher dose with a lower Cmax, a recent analysis showed the 3-hour schedule to be safe at the recommended dose of 1,300 µg/m2 and may be a potential alternative outpatient schedule that requires additional validation [17,19,22,40,41,46]. In conclusion, this study shows that the 24-hour continuous ET-743 infusion regimen is feasible and shows encouraging disease control in highly pretreated, progressing, advanced, metastatic, and resistant or refractory sarcoma patients. These results confirm the relevance and consistency of previous observations of ET-743 activity in patients with advanced STS [35,36]. Our data show that beyond the consistent but low ORR in STS patients who are refractory to standard treatment, the 24-hour ET-743 infusion regimen induces tumor control in 24% of patients for at least 6 months, and a small proportion of patients were rendered tumor free by the sequential combination of ET-743 and salvage surgery. Our results also demonstrate that ET-743 is feasible in STS without the need for concomitant therapy with hematologic growth factors. ET-743 is a representative example of a new class of anticancer agents. Additional development in sarcoma as a single agent or in combination is warranted.
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): C. Martin, PharmaMar; J. Jimeno, PharmaMar. Acted as a consultant within the last 2 years: E. Cvitkovic, CAC; J.L. Misset, Hôpital St Louis. Performed contract work within the last 2 years: E. Cvitkovic, CAC; A. Yovine, CAC; Y. Salhi, CAC. Received more than $2,000 a year from a company for either of the last 2 years: E. Cvitkovic, CAC; C. Martin, PharmaMar; J. Jimeno, PharmaMar.
We gratefully acknowledge the assistance of Elizabeth Cory in preparing the manuscript.
Supported by PharmaMar SA and part of the 5th EU Framework Anticancer Program in the framework of the European Union BIOMED II Lifesciences Demonstration Project BMH4-CT98-3614. Presented in part at the 36th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
