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© 2001 American Society for Clinical Oncology Ecteinascidin-743: A Marine-Derived Compound in Advanced, Pretreated Sarcoma Patients—Preliminary Evidence of ActivityFrom the Hôpital Paul Brousse and Institut Gustave Roussy, Villejuif; CAC, Kremlin Bicêtre; Centre René Huguenin, Saint Cloud; Hôpital Saint Louis, Paris, France; and Pharma Mar SA Clinical Research and Development, Madrid, Spain. Address reprint requests to Esteban Cvitkovic, MD, Hôpital Paul Brousse, 12-14 boulevard Paul Vaillant Couturier, 94800 Villejuif, France; email: e.cvitkovic{at}cvitkovic-ac.fr
PURPOSE: To report the activity of the chemotherapeutic agent ecteinascidin-743 (ET-743) in advanced pretreated sarcoma patients observed during a phase I study and a named-patient basis, compassionate use program. PATIENTS AND METHODS: Twenty-nine pretreated, advanced soft tissue sarcoma (STS) and bone sarcoma patients consecutively seen in our centers were included, 12 from a phase I trial and 17 from a compassionate use program cohort. Patients were treated every 3 weeks at either 1,200 µg/m2 (six patients), 1,500 µg/m2 (the recommended dose, 22 patients), or 1,800 µg/m2 (the maximum-tolerated dose, one patient), given as a 24-hour infusion every 3 to 4 weeks. RESULTS: Fifteen men and 14 women were treated. The median patient age was 46 years (range, 16 to 71 years), with a median World Health Organization performance status of 1 (range, 0 to 2). Twenty-five patients had STS, three had osteosarcoma, and one had Ewing’s sarcoma, and all had progressive disease at accrual. Fifteen patients had bulky disease, and 14 had clinical resistance to anthracyclines. A total of 136 treatment cycles were administered (median per patient, five cycles; range, one to 12 cycles). Transient grade 3 and 4 transaminitis was reported in 24% and 5% of cycles, respectively, grade 3 to 4 neutropenia occurred in 32% of cycles, with concomitant sporadic grade 3 to 4 thrombocytopenia in 5.1% of cycles. Grade 2 to 3 asthenia occurred in 21% of cycles. There were two partial responses (PRs) in STS patients and two PRs in osteosarcoma patients. Two minor responses and 10 disease stabilizations were seen. Median duration of response was 10.5 months (range, 2.8 to 15 months), and mean duration of stabilization was 5.2 months. CONCLUSION: ET-743 has activity in advanced, highly pretreated STS and osteosarcoma patients and warrants further trials to establish the extent of its activity in this setting.
ADULT SOFT tissue sarcomas (STSs) belong to a rare, heterogeneous family of malignancies, accounting for approximately 1% of all adult tumors. Currently, despite adequate control of the primary tumor, more than half of all patients die within 5 years of the primary diagnosis, as a result of widespread metastatic disease.1 In the majority of trials evaluating mono- or polychemotherapy treatment, median survival time after diagnosis of metastasis has been reported to be less than a year.2,3 Inoperable or metastatic sarcomas of osseous origin, such as osteogenic and Ewing’s sarcomas, are generally fatal, typically showing low responsiveness to chemotherapy, although a few selected patients have undergone successful pulmonary metastasis resection.4,5 Only a few chemotherapeutic agents have shown activity in more than 15% of advanced STS patients. Doxorubicin remains the reference drug for first-line treatment, with a single-agent cumulative response rate of approximately 25%.3,6 DNA interacting agents including high-dose ifosfamide, cisplatin, and dacarbazine also display low to moderate activity in this setting.7-11 Clinical, biologic, and recent molecular biology determinants of chemoresistance such as MDR expression or mutated p53 have been described and validated.12,13 Because second-line single-agent or combination regimens result in very few responses, patients who fail to respond or who relapse after anthracycline-based regimens are considered to be suitable for new investigational drugs or strategies.14,15 Similar observations have been made among advanced, relapsing, anthracycline-, alkylator-, and methotrexate-resistant osteosarcoma, and Ewing’s sarcoma patients.16 Clearly, active new agents for these patients are needed. Ecteinascidin-743 (ET-743) is a recently identified compound, isolated from the Caribbean marine tunicate Ecteinascidia turbinata.17 This tetrahydroisoquinolone alkaloid is a DNA guanine-specific minor groove binding agent,18 which blocks the cell cycle in late S and G2 phases and affects the organization and assembly of the microtubule network.19 Pharmacologic concentrations of ET-743 have been shown to block gene transcription in a promoter-specific manner.20,21 ET-743 has shown high preclinical activity against a number of human solid tumor cell lines and xenografts, including sarcomas, showing low or no cross-resistance with several standard chemotherapeutic agents.22,23 Administration of ET-743 at the maximum-tolerated dose (MTD) for different time exposures induced complete regressions in non–small-cell lung carcinomas (LXFL529), melanomas (MEXF 89), and ovarian (HOC22) cancer human xenografts.24,25 In addition, ET-743 induced a partial tumor regression in a chemoresistant (although marginally cisplatin-sensitive) ovarian carcinoma xenograft (HOC18).25 Our phase I trial using a 24-hour continuous-infusion schedule of this agent established an MTD of 1,800 µg/m2, and a recommended dose (RD) for low-risk patients of 1,500 µg/m2, administered every 21 days.26 The principal dose- and treatment-limiting toxicities observed in this phase I trial were severe neutropenia and thrombocytopenia. Moderate or severe acute, postdosing, transient transaminitis was prevalent but never treatment limiting.26 The observation of one objective response and unexpected disease stabilizations among STS and bone sarcoma patients treated in the phase I trial prompted the initiation of phase II programs in advanced STS. Meanwhile, on the basis of our promising results in the phase I trial, a number of patients who were ineligible for phase II trials were treated with ET-743 on an investigator-originated, named-patient basis, compassionate use program. We report here the results of our combined experience with advanced, metastatic, highly pretreated, STS and bone sarcoma patients treated with ET-743 in the phase I trial and the compassionate use program.
Patient Population The present report considers two patient cohorts. Advanced, refractory sarcoma patients were included in the phase I trial between May 1996 and December 1998. In 1999, all patients referred to our institutions who were not eligible for the subsequent, and still ongoing, phase II trial because of histology (bone sarcomas) or previous treatment (more than one previous regimen), were treated with ET-743 (supplied by Pharma Mar, Madrid, Spain) in a named-patient basis, compassionate use program. Inclusion into this program required both the approval of the regulatory body (the Agence Française de Régulation Sanitaire) after an individual request by the treating physician, as well as clearance by Pharma Mar. All patients eligible for either the phase I trial and the compassionate use program were required to have histologically proven, advanced metastatic disease, have been previously treated with conventional chemotherapy regimens including anthracyclines, and have documented disease progression within 4 weeks before study entry. All patients gave written informed consent before accrual. Patients included in the phase I trial had to be more than 18 years old, have a World Health Organization (WHO) performance status (PS) less than 2, an expected survival more than 3 months, normal renal function (serum creatinine within normal limits), adequate bone marrow reserve (absolute granulocyte count > 2,500/µL, platelet count > 100,000/µL, and hemoglobin levels > 10 g/L), and liver biologic function tests (alkaline phosphatase [AP], AST, ALT, and bilirubin) within normal limits.
The same inclusion criteria applied to patients entered onto the compassionate use program, with the exception of age (one 16-year-old patient was included with parental authorization), PS (PS = 2 accepted), hemoglobin levels (not considered), and AST/ALT/AP, and bilirubin (up to 2.5 x upper limits of normal). Elevated AP and bilirubin levels ( Anthracycline clinical resistance has long been recognized in sarcoma patients and may correlate with MDR gene expression.12 Large disease volume in single targets (bulkiness) leads to major difficulties in achieving WHO-Union Internationale Contre le Cancer28–defined clinical responses (a decrease > 50% in the product of the diameters). Thus, we further categorized our population in terms of anthracycline resistance, defined as progression occurring while under anthracycline-containing treatment, irrespective of best response; and bulky disease, defined as the existence of at least one tumor mass with a diameter of at least 10 cm.
Treatment Plan Patients from the phase I trial who were considered in this report were those treated at the three highest dose levels assessed. Three patients received an initial dose of 1,200 µg/m2, eight patients were treated at the phase II RD of 1,500 µg/m2, and one was treated with 1,800 µg/m2, established as the phase I trial MTD. Three patients included in the compassionate use program received 1,200 µg/m2, and 14 patients received the RD of 1,500 µg/m2. Treatment cycles were repeated every 3 weeks. No prophylactic hematopoietic growth factor support was allowed. In cases of insufficient hematologic recovery or hepatic values that had not returned to baseline on day 1 of any cycle, treatment was delayed until the neutrophil count reached more than 1,500/µL, the platelet count reached more than 100,000/µL, and hepatic tests had returned to baseline. In cases of an absence of recovery by day 42, the patient was withdrawn from the study unless there appeared to be clinical benefit. In cases of grade 4 neutropenia lasting more than 7 days, febrile neutropenia lasting more than 3 days, and grade 4 thrombocytopenia requiring platelet transfusion, the ET-743 dose was reduced to the next lowest dose level (ie, 1,500 µg/m2 if the patient was treated at 1,800 µg/m2, and 1,200 µg/m2 if the patient was treated at 1,500 µg/m2). Treatment was continued until disease progression, unacceptable toxicity, or patient refusal. In cases of good tolerance for patients initially treated at a dose of 1,200 µg/m2 in the compassionate use program, the treatment dose could be increased after the first cycle to 1,500 µg/m2. Antiemetic prophylaxis, including HT3 receptor agonists and oral metoclopramide (60 mg/d), was administered on days 1 to 3. In addition, corticosteroids were administered, on occasion, to compassionate use cohort patients. A complete blood cell count was performed twice weekly, and was repeated every day in cases of grade 4 neutropenia or thrombocytopenia, until recovery. Liver and renal tests (AP, ALT, AST, bilirubin, and serum creatinine) were also performed twice weekly. Toxicity was evaluated according to National Cancer Institute common toxicity criteria by clinical and laboratory evaluations at each cycle. WHO criteria were used for assessment of partial response (PR) and complete response. The category of minor response (MR), defined as a 25% to 50% decrease in the product of the diameters of measurable target lesions, was also assessed, with stable disease (SD) defined as a decrease or increase of less than 25% in the measurable lesions lasting at least 2 months. Tumor evaluation was carried out every two cycles with the appropriate clinical and the same radiologic examinations.
Patient Characteristics Patient characteristics are listed in Table 1. A total of 29 patients were treated, 12 patients in the phase I trial and 17 in the compassionate use program. Distribution of sex, histology, and involved site distribution did not differ markedly between the two groups. All patients had previously received both anthracyclines and alkylators. Several had also received cisplatin treatment, as well as other cytotoxic agents. Three patients had previously undergone high-dose chemotherapy with stem cell support (one with ifosfamide, carboplatin, and etopside and two with cyclophosphamide and epirubicin). The median number of previous chemotherapy regimens for all patients was three (range, one to six regimens), with 48% of the patients being resistant to anthracyclines and 52% having bulky disease.
Treatment Exposure A total of 136 treatment cycles were administered. The median number of cycles administered per patient was five (range, one to 12 cycles). Thirteen patients (45%) received two cycles or less, all withdrawing because of early progression. No treatment withdrawals were caused by toxicity. Sixteen patients (55%) received at least four cycles. Dose reductions were necessary in seven patients (24%), six of which were because of hematologic toxicity (grade 4 neutropenia, one of which was febrile) and one of which was because of persistent transaminitis (grade 1) before the fifth cycle. All three patients on the compassionate use program treated with an initial dose of 1,200 µg/m2 showed good tolerance in the first cycle, so their subsequent treatment dose per cycle was increased to 1,350 µg/m2.
Safety
Efficacy As of April 1, 2000, all 29 treated patients were assessable for response. The best responses observed, response duration, and histologic characteristics of the responding patients are listed in Table 3. Overall, four PRs (14%), two MRs (6.9%), with tumor reduction 30% or greater in both cases, and 10 patients with SD lasting more than 2 months (34%) were noted. Thirteen patients (45%) showed outright progression at the first evaluation (ie, after two treatment cycles).
The median time to progression was 2.8 months (95% confidence interval, 2.15 to 15+). The median duration of response (including MR) was 10.5 months (range, 2.8 to 15+ months), and of disease stabilization was 5.2 months (range, 3 to 12 months). At a median follow-up time of 12.2 months (range, 9.5 to 34 months), the median overall survival of the cohort was 7.8 months, with 13 patients alive, seven of them alive at follow-up greater than 1 year. Table 3 shows that responding patients had histologies of osteosarcoma (two patients), fibrosarcoma (one patient), and liposarcoma (one patient). It is of note that of the three osteosarcoma patients treated, two had objective responses. Three patients with previously unresectable disease (two with PR, one with MR) were amenable to complete macroscopic resection after six to eight cycles of treatment. One of the resected patients had a fatal massive bleeding immediately after large pulmonary resection of bulky metastases. A patient with osteosarcoma remained free of disease for 8 months, after resection of pleuropulmonary disease subsequent to a PR. One patient showed no evidence of disease 6 months after resection of a voluminous recurrent abdominal liposarcoma performed after a clear MR after eight cycles of treatment. One patient with a liposarcoma of the spermatic cord, with liver, bone, and skin metastases, still showed a PR after 12 cycles of treatment and a further 4 months off treatment. Disease stabilizations were noted in diverse histologic subtypes (Table 3). Among eight leiomyosarcoma patients, four had disease progression, whereas one patient had an MR and three had SD lasting more than 2 months. Responses were seen at all reported disease sites, including hepatic metastases and pleuropulmonary metastases. One PR lasting for more than 15 months and four clinically meaningful stabilizations in previously progressing patients were reported in 14 anthracycline-refractory patients ( Table 4). Responses were also observed among patients with bulky disease (two PR, one MR, and six SD patients, out of 15 patients) as well as nonbulky disease (two PR, one MR, and four SD patients, out of 14 patients). All PRs and MRs were seen in patients treated with 1,500 µg/m2, as was the case with six of the nine stabilizations.
These preliminary results of ET-743 treatment of patients with advanced STS and bone sarcomas are promising, showing that this agent deserves further assessment. Indeed, although anthracycline-based chemotherapy regimens show established activity as a first-line treatment in adult relapsed, metastatic, advanced STS, most agents used in second-line or further therapies are disappointing. Given the prevalence of the use of anthracyclines as adjuvant or first-line treatment, their potential reintroduction in the treatment of advanced pretreated sarcoma patients is precluded by a high risk of congestive heart failure. Although very-high-dose continuous infusion ifosfamide showed interesting response rates in this context (overall response rate, 35% to 39%),8,9 these rates have not been confirmed in more recent trials7 (overall response rate, 16%). Furthermore, the response rates were associated with the need for very close monitoring and high morbidity rates. Newly introduced anticancer agents have been explored in this indication, with disappointing results. Taxanes, and particularly docetaxel, showed promising early activity in initial phase II trials,29 which, however, was not confirmed in subsequent studies.7,30,31 Vinorelbine, topoisomerase I inhibitors, temozolomide, and gemcitabine all showed encouraging results in early reports; however, recent phase II trials failed to confirm significant activity.30,32-37 In this report, we show responses and disease stabilizations among a cohort of very advanced and highly pretreated progressive sarcoma patients. The median duration of disease stabilization (5.2 months) and of response (10.5 months), compare well with typical phase II trial results in this subset of patients with highly pretreated, advanced sarcomas of various types. Interestingly, the responses and stabilizations observed in our cohort were seen in sarcomas of various histologies, including the usually chemorefractory leiomyosarcomas2 and gastrointestinal stromal tissue tumors. Furthermore, we observed responses in two of three patients with advanced osteosarcoma, a disease for which there has been no reported activity of a new chemotherapeutic single agent for several years. The 10 stabilizations observed among STS patients can be considered as indirect and minor evidence of the antitumoral effect of ET-743 in this family of diseases. Indeed, although the clinical significance of disease stabilization in STS has not been clearly established, it is noteworthy that all patients had documented disease progression at the time of entry. Responses and stabilizations were observed in bulky as well as nonbulky disease. In addition, there was one objective response in an anthracycline-refractory sarcoma patient. This observation supports the in vitro observations of non–cross-resistance of ET-743 with many anticancer compounds.22 We observed responses at all reported disease sites, including liver, despite the fact that liver involvement is usually acknowledged as a negative predictive factor of response to chemotherapy.2 Two of four partial responders were treated in the compassionate use program. One might argue that this cohort of patients was referred for such a program on the basis of younger age and good general condition, both of which have been shown to positively influence response rates in standard chemotherapy for STS.2 The median age of patients in the compassionate use cohort study was 42 years, which is younger than that usually observed for mixed STS patients. The three osteosarcoma patients, of whom two responded, were both younger than 20 years old. However, performance status was not different in our patients compared with other published studies, although eight of 17 patients in the compassionate use patient cohort were PS 2, and no patients in the phase I study had a poor general condition. Furthermore, compassionate use program patients had heavier pretreatment characteristics than the phase I experience cohort with, respectively, a median number of three and one previous chemotherapeutic regimens. Complementary surgery in the present cohort of highly pretreated advanced sarcoma patients was effective, as tumors in three patients with objective responses were rendered resectable after six to nine treatment cycles of ET-743. All three patients had a macroscopically complete disease resection, and two are long-term survivors after resection of a bulky pulmonary tumor and a very extensive abdominal tumor mass. The role of surgical resection in responding patients, as the only potentially curative modality, has already been underscored.4,5 The toxicities encountered in these cohort studies were manageable. A detailed pharmacokinetic-pharmacodynamic and safety-morbidity analysis is available in the phase I trial report. Phase I toxicity data were confirmed in the compassionate use cohort, with the dose-limiting toxicity being neutropenia. Highly pretreated patients experienced few episodes of grade 3 to 4 neutropenia and grade 2 to 3 asthenia. Transaminitis, as previously described, was transient, and tended to decrease in intensity in later cycles. Increased baseline levels of alkaline phosphatase, reflecting liver involvement and intrahepatic cholestasis, have been described as a potential prospective predictor of ET-743–induced dose-limiting toxicities.27 This, however, could not be confirmed in our cohort because of an insufficient number of patients. Other toxicities were mild and included grade 2 to 3 nausea and vomiting in 20% of the cycles, usually of short duration and reversible under antiemetic therapy. Asthenia was also transient during cycles and rarely interfered with the patients’ quality of life. Its higher prevalence amongst the compassionate use cohort patients is likely to be related to their poorer PS and heavier pretreatment characteristics. In conclusion, this combined report of patients from a phase I study and from a compassionate use cohort shows that the regimen of 24-hour continuous ET-743 infusion is active and feasible among highly pretreated, advanced, metastatic and refractory sarcoma patients, and confirms the phase I toxicity profile. Promising ET-743 activity in this subset of STS and osteosarcoma patients has prompted the initiation of ongoing European and United States trials. It is of particular interest that the preliminary results of these trials confirm our previous observations of activity in patients with advanced STS.38,39
We thank Dr Sarah Mackenzie for her collaboration and help in editing the manuscript.
Presented in part at the 10th European Cancer Conference, September, 12-16, 1999, Vienna, Austria; the AACR-NCI-EORTC International Conference, November, 16-19, 1999, Washington, DC; and the 36th Annual Meeting of the American Society of Clinical Oncology, May 20-23, 2000, New Orleans, LA.
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Bramwell V, 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 31. Patel SR, Linke KA, Burgess MA, et al: Phase II study of paclitaxel in patients with soft tissue sarcoma. Sarcoma 1: 95-97, 1997 32. Fidias P, Demetri G, Harmon DC: Navelbine shows activity in previously treated sarcoma patients: Phase II results from MGH/DANA Farber/Partner’s Cancer Care Study. Proc Am Soc Clin Oncol 17: 513a, 1998 (abstr) 33. Rankin C, Budd GT, Hutchins L, et al: SWOG 9518: Phase II trial of continuous infusion topotecan in patients (Pts) with advanced soft tissue sarcomas (STS). Proc Am Soc Clin Oncol 17: 523a, 1998 (abstr) 34. De Angelo DJ, Naujoks RA, Manola J, et al: Phase II study of irinotecan (CPT-11) in relapsed or refractory soft tissue sarcoma (STS). Proc Am Soc Clin Oncol 19: 555a, 2000 (abstr) 35. Taub RN, Koehan M, Plitsas M, et al: Phase II study of temozolomide in advanced sarcomas. Proc Am Soc Clin Oncol 19: 555a, 2000 (abstr) 36. Woll PJ, Judson I, Lee SM, et al: Temozolomide in adult patients with advanced soft tissue sarcoma: A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 35: 410-412, 1999 37. Okuno SH, Edmonson JH, Mahoney MR, et al: Limited activity and acceptable toxicity of gemcitabine in a phase II study of patients (Pts) with advanced sarcoma: A Mayo Cancer Center Study. Proc Am Soc Clin Oncol 19: 555a, 2000 (abstr) 38. Le Cesne A: Phase II study of ET-743 in advanced soft tissue sarcoma (ASTS) in adults: A STBSG-EORTC trial. Proc Am Soc Clin Oncol 19: 554a, 2000 (abstr) 39. Demetri GD, Seiden M, Garcia-Carbonero R: Ecteinascidin (ET-743) shows promising activity in distinct populations of sarcoma patients: Summary of 3 US-based phase II trials. Proc Am Soc Clin Oncol 19: 553a, 2000 (abstr) Submitted July 7, 2000; accepted November 7, 2000. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
grade 1) are prognostic factors for its toxicity likelihood.
