Activity In Soft Tissue Sarcoma Research Articles

New Developments in Targeted Therapy for Soft Tissue Sarcoma

Soft tissue sarcomas (STS) are rare diseases, with an estimated 10,390 new cases in the United States in 2008. Unfortunately, only 50% are cured with surgical resection. The standard cytotoxic chemotherapeutic agents have not been successful in the treatment of metastatic disease. The standard single-agent chemotherapy for metastatic disease is doxorubicin, with only 20% to 25% response rates. The combination of doxorubicin with other agents, such as ifosfamide, has improved response rates, without any improvement in overall survival. New targeted therapies have shown some activity in STS; however, disease stabilization is seen more often than a true radiographic response. The combination of cytotoxic chemotherapy with more targeted and novel agents may be appropriate to improve outcome in these patients. The agents of interest in sarcomas at this time are multi-tyrosine kinase inhibitors, antiangiogenesis agents, inhibitors of mammalian target of rapamycin, hypoxia-activating prodrugs, insulin growth factor monoclonal antibodies, and tumor necrosis factor-related apoptosis-inducing ligand agonists.

“Metronomic” chemotherapy in advanced soft tissue sarcomas

Angiogenesis plays a crucial role in metastatic progression of soft tissue sarcomas (STS). Endothelial cells are the primary target of metronomic chemotherapy. We report the safety and the efficacy of metronomic chemotherapy in metastatic STS patients. The medical charts of 26 metastatic STS patients treated at Institut Bergonie (Bordeaux, France) with metronomic etoposide (100 mg/day orally for 21 consecutive days, repeated every 4 weeks) were reviewed by two independent investigators. Median age was 49. All but three patients received prior treatment with doxorubicin and/or ifosfamide. One patient (4%) had partial response and 11 patients (42%) had stable disease for more than 24 weeks. The 6-month and the 1-year progression-free survival rates were 42% [95% CI: 23; 61] and 23% [95% CI: 7; 39], respectively. The 6-month and the 1-year overall survival rates were 69% [95% CI: 51; 87] and 31% [95% CI: 13; 49], respectively. Two patients experienced grade 4 febrile neutropenia and one of them died of sepsis. In this series, metronomic etoposide was associated with significant clinical activity in STS. Further prospective investigations are necessary to identify those patients who are more likely to benefit from this strategy.

Efficacy and safety of sorafenib in a subset of patients with advanced soft tissue sarcoma from a Phase II randomized discontinuation trial

Phase II multi-disease randomized discontinuation trial to assess the safety and efficacy of sorafenib including patients with advanced soft tissue sarcoma (STS). Sorafenib (400 mg twice daily) was initially administered for 12 weeks. Patients with: ≥25% tumour shrinkage continued sorafenib; ≥25% tumour growth discontinued; other patients were randomized and received sorafenib or placebo. Twenty-six patients (median age 55 years) were enrolled. Common drug-related adverse events, including fatigue, hand-foot skin reaction, rash or gastrointestinal disturbances, were manageable, reversible and generally low grade. Fatigue, skin toxicity, nausea, diarrhoea and hypertension occurred at grade ≥3 in 19% of patients. After 12 weeks eight (31%) patients had not progressed. Three patients who experienced tumour shrinkage and continued on sorafenib, and five (19%) were randomized either to continue sorafenib or to receive placebo. Of the three patients randomized to sorafenib, one achieved a partial response and two had SD. Overall one patient achieved a partial response and three further patients achieved minor responses. There was evidence of disease activity in STS as defined by tumor regressions including one objective partial response. Further investigation in STS is warranted.

Combining PCI-24781, a Novel Histone Deacetylase Inhibitor, with Chemotherapy for the Treatment of Soft Tissue Sarcoma

Histone deactylase inhibitors (HDACi) are a promising new class of anticancer therapeutics; however, little is known about HDACi activity in soft tissue sarcoma (STS), a heterogeneous cohort of mesenchymal origin malignancies. Consequently, we investigated the novel HDACi PCI-24781, alone/in combination with conventional chemotherapy, to determine its potential anti-STS-related effects and the underlying mechanisms involved. Immunoblotting was used to evaluate the effects of PCI-24781 on histone and nonhistone protein acetylation and expression of potential downstream targets. Cell culture-based assays were utilized to assess the effects of PCI-24781 on STS cell growth, cell cycle progression, apoptosis, and chemosensitivity. Quantitative reverse transcription-PCR, chromatin immunoprecipitation, and reporter assays helped elucidate molecular mechanisms resulting in PCI-24781-induced Rad51 repression. The effect of PCI-24781, alone or with chemotherapy, on tumor and metastatic growth was tested in vivo using human STS xenograft models. PCI-24781 exhibited significant anti-STS proliferative activity in vitro, inducing S phase depletion, G(2)/M cell cycle arrest, and increasing apoptosis. Superior effects were seen when combined with chemotherapy. A PCI-24781-induced reduction in Rad51, a major mediator of DNA double-strand break homologous recombination repair, was shown and may be a mechanism underlying PCI-24781 chemosensitization. We showed that PCI-24781 transcriptionally represses Rad51 through an E2F binding-site on the Rad51 proximal promoter. Although single-agent PCI-24781 had modest effects on STS growth and metastasis, marked inhibition was observed when combined with chemotherapy. In light of these findings, this novel molecular-based combination may be applicable to multiple STS histologic subtypes, and potentially merits rigorous evaluation in human STS clinical trials.

Evaluation of Human Plasma Protein Binding of Trabectedin (Yondelis™, ET-743)

Trabectedin (ET-743, Yondelis) is a novel anticancer drug with impressive activity in soft tissue sarcoma with a manageable, non-cumulative toxicity profile. Protein binding can be a major determinant of unbound concentration, volume of distribution, renal and hepatic clearance, and the half-life of a drug. Human plasma protein binding of trabectedin has not previously been reported. Using ultrafiltration techniques, we determined the human plasma protein binding of trabectedin at a clinically relevant concentration. Experiments with a panel of co-medications representing all known protein-binding sites showed that the concentration of unbound trabectedin could be increased by high concentrations of phenytoin. The other tested co-medications, at concentrations covering their respective therapeutic ranges, did not displace trabectedin from its plasma protein binding. This suggests that trabectedin binds to albumin site I (total protein binding of 94.2 +/-0.6 %) displaying an association constant of 2.6 +/-0.2 10(4) M(-1). Because trabectedin is an intermediate-to-high hepatic extraction drug, changes in unbound fraction will not have a major impact on elimination processes. The high protein binding may have implications for the interpretation of in vitro data, which are usually performed in the presence of low protein levels. We can conclude that the studied co-medications are unlikely to have clinically relevant effects on trabectedin binding to plasma proteins at therapeutic concentrations.

Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer

The combination of trabectedin (T) and doxorubicin (D) was brought into clinical development in soft tissue sarcoma (STS) and advanced breast cancer (ABC) because of its in vitro and in vivo additive anti-tumour effect, the fact that there are no overlapping toxicities and the anti-tumour activity of T in those tumours. Feasibility and anti-tumour activity of T+D administered every 3 weeks were evaluated in 38 patients (STS=29, ABC=9) untreated for advanced disease. D was given at 60mg/m2 and T at escalating doses from 600 to 800μg/m2, which was the maximum tolerated dose due to dose-limiting febrile neutropenia and asthenia. The recommended dose - given to 18 patients in total - was 700μg/m2 T with 60mg/m2 D. The pharmacokinetic profile of T and D at cycle 1 was analysed in 20 patients. The most common toxicities included a severe but reversible ASAT/ALAT increase (94%), nausea/vomiting, neutropenia, asthenia/fatigue, stomatitis. Partial response and stable disease were assessed in 18% and 56% of STS patients and in 55% and 33% of ABC patients. No pharmacokinetic interaction between T and D was observed. The lack of cumulative toxicity and related complications and the promising activity in STS support further development of T+D.

Randomized, Phase II Study of the Thrombospondin-1-Mimetic Angiogenesis Inhibitor ABT-510 in Patients With Advanced Soft Tissue Sarcoma

Sarcomas are among the most proangiogenic malignancies in preclinical models. Phase I study results for ABT-510, which inhibits angiogenesis via a novel thrombospondin-mimetic mechanism, suggested activity in soft tissue sarcoma (STS) patients. This phase II study further evaluated the safety and efficacy of ABT-510 in advanced STS patients. Patients with metastatic or unresectable STS were randomly assigned to treatment with one of two ABT-510 dose schedules (20 mg once a day [20 mg], n = 42; or 100 mg twice a day [200 mg], n = 46), which were self-administered subcutaneously in 28-day treatment periods. End points included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and safety. Median PFS for the 20-mg arm was 94 days, with 4- and 6-month PFS rate estimates of 42% and 24%, respectively. Median PFS for the 200-mg arm was 64 days, with 4- and 6-month PFS rate estimates of 41% and 32%, respectively. Although only one objective response was noted, stable disease was observed in 52% (20 mg) and 48% (200 mg) of patients. Median OS was 431 days (20 mg) and 295 days (200 mg). ABT-510 was well tolerated. Rare treatment-related grade 3 or 4 adverse events were one event each of hypotension, deep vein thrombosis, and hypophosphatemia. ABT-510 pharmacokinetics were dose proportional, time independent, and consistent with those in previous studies. ABT-510 had a favorable safety profile, and the rate of disease control and OS times were encouraging. However, with low ORR and lack of dose response, the study failed to yield compelling evidence of strong single-agent activity in STS.

Preliminary efficacy and safety results of glufosfamide (GLU) in relapsed soft tissue sarcoma: Results of a phase II trial

10591 Background: Glufosfamide is glucose linked to isophosphoramide mustard, the active metabolite of ifosfamide. Ifosfamide is known to have activity in soft tissue sarcoma. The objectives of this study are to evaluate the safety and efficacy of GLU in patients (pts) with soft tissue sarcoma. Methods: This 1-stage phase 2 study planned to enroll 22 pts with metastatic and/or advanced unresectable soft tissue sarcoma previously treated with 1–2 prior systemic therapies. Prior ifosfamide was allowed unless most recent relapse occurred within 4 weeks of completion of ifosfamide. Pts received GLU 5000 mg/m2 IV over 1 hour every 21 days for up to 6 cycles. Primary endpoint was confirmed response rate. FDG PET scans were collected prior to Cycle 3 if PET positive at baseline. Results: 11 male/11 female pts enrolled; 2 did not meet all eligibility criteria. Median age 52 y (range: 19–77); ECOG 0/1 (16) and 2 (6). Histology: leiomyosarcoma (8), synovial (5), angiosarcoma (3), other (6). Four pts completed 6 cyc...

Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study

Previous studies have suggested that trabectedin (ecteinascidin-743) could have antitumour activity in soft-tissue sarcoma. We aimed to study the usefulness of trabectedin in the treatment of patients with myxoid liposarcomas, a subtype of liposarcoma that is associated with specific chromosomal translocations t(12;16)(q13;p11) or t(12;22)(q13;q12) that result in the formation of DDIT3-FUS or DDIT3-EWSR1 fusion proteins. 51 patients with advanced pretreated myxoid liposarcoma who started treatment with trabectedin between April 4, 2001, and Sept 18, 2006 at five institutions in a compassionate-use programme were analysed retrospectively. Centralised radiological and pathological reviews were done for most patients. Trabectedin was given either as a 24-h continuous infusion or as a 3-h infusion, every 21 days, at 1.1-1.5 mg(2). 558 courses of trabectedin were given in total, with a median of ten courses for each patient (range 1-23). The primary endpoints were response rate and progression-free survival, and the secondary endpoint was overall survival. According to Response Evaluation Criteria in Solid Tumors (RECIST), after a median follow-up of 14.0 months (IQR 8.7-20.0), two patients had complete responses (CR) and 24 patients had partial responses (PR); the overall response was 51% (95% CI 36-65). Five patients had early progressive disease. In 17 of the 23 patients who achieved PR or CR as defined by RECIST and who had centralised radiological review, tissue-density changes, consisting of a decrease in tumour density on CT scan or a decrease in contrast enhancement on MRI (or both), preceded tumour shrinkage. Median progression-free survival was 14.0 months (13.1-21.0), and progression-free survival at 6 months was 88% (79-95). Trabectedin was associated with antitumour activity in this series of patients with myxoid liposarcoma. The noted patterns of tumour response were such that tissue density changes occurred before tumour shrinkage in several patients. In some patients, tissue-density changes only were seen. Long-lasting tumour control was noted in responsive patients. The compassionate-use programme is still ongoing. This analysis has resulted in the initiation of two prospective studies to assess the role of trabectedin in the treatment of patients with myxoid liposarcoma in preoperative and metastatic settings. Furthermore, the selective mechanism of action for trabectedin in this translocation-related sarcoma is being studied.

ET 743 is an effective agent against sarcoma

20516 Background: ET-743 has shown clinical activity in soft tissue sarcoma after failure of anthracyclines and ifosfamide. We propose to assess these results in our institution. Methods: We reviewed the patients treated (in phase II studies or on a compassionate basis) until June 2006 Results: Median age of the 99 patients was 53 years (18–82, with 20% leiomyosarcomas, 18% other spindle cell sarcomas, 12% liposarcomas, 9% osteosarcomas and 4% Ewing's sarcomas. The initial tumor was in the lower limbs in 31% of cases, and 70% had lung metastases. Patients had received anthracyclines (72%) or ifosfamide (61%), but 12% received ET-743 as their 1st chemotherapy. Most patients received ET-743 as a single agent, but 7 received it in combination with doxorubicin. After a median of 4 cycles (1–25), 50% of patients responded: 0 CR, 12 patients with PR, 4 MR (minor response), 34 SD and 49 progressed. Median time to progression for patients with a clinical benefit (PR+MR+SD) was 7 months (1.5 to 66 months). Among the 29 patients who didn't progress in the first six months, 10 had leiomyosarcomas and 8 spindle cell sarcomas. Grade3/4 toxicity, mainly hematological (42% neutropenia, 16% anemia, 11% thrombocytopenia) and hepatic (33%), was noted in 69 patients (28 needed a dose reduction). Main cause of treatment discontinuation was progression (70%) but 7 patients had to stop treatment because of toxicity. Conclusions: ET- 743 can benefit some patients with sarcomas, especially leiomyosarcomas, even pretreated. Some patients have long lasting responses. Grade ¾ toxicity is frequent but rarely leads to treatment discontinuation No significant financial relationships to disclose.

Phase II study of intravenous TZT‐1027 in patients with advanced or metastatic soft‐tissue sarcomas with prior exposure to anthracycline‐based chemotherapy

TZT-1027, a novel chemotherapeutic agent, is derived from dolastatin 10, and blocks cells during G2/M-phase by interfering with microtubule assembly and stability. TZT-1027 has exhibited potential cytotoxic activity in several human cancer cell lines (in vitro) and also demonstrated antitumor activity in human xenografts (in vivo). In addition, Phase I clinical investigations suggested activity in STS (soft-tissue sarcoma). Eligible patients were those who had histologic evidence of locally advanced or metastatic STS and who had received 1 prior treatment regimen with an anthracycline-based chemotherapy for metastatic disease. Subjects received intravenous infusions of TZT-1027 over 1 hour on Day 1 and Day 8 of each 21-day treatment course. Efficacy was evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Twenty-nine patients were enrolled and 28 patients received at least 1 course of study drug and were eligible for efficacy and safety evaluation. The median age of the patients was 48 years (range, 23-73 years) and the median baseline Eastern Cooperative Oncology Group (ECOG) performance status was 1 (range, 0-2). A total of 67 courses (range, 1-9 courses; median, 2 courses) of TZT-1027 were administered. No patient in the study demonstrated an objective response to treatment. Of 6 patients (21.4%) who experienced disease stabilization, 1 continued to have stable disease for 9.3 months. The median time to tumor progression was 44 days (95% confidence interval [95% CI], 43.0-54.0) and the median survival was 178 days (95% CI, 134.0-317.0). The most commonly reported toxicities were neutropenia, fatigue, and constipation. TZT-1027 was found to be safe and well tolerated, and the hematologic toxicities observed were consistent with preclinical toxicology and Phase I study findings. No confirmed responses were seen in the current study.

ET-743: a novel agent with activity in soft-tissue sarcomas

ET-743 (ecteinascidin-743, trabectedin, Yondelis) is a natural marine product that has shown clinical activity in sarcoma. This paper reviews the current knowledge on this compound. ET-743 interferes with several transcription factors, traps protein from the nucleotide-excision repair system, thus resulting in DNA damage, modulates gene expression, and blocks cells in the G2-M phase. In the clinical setting, after failure of standard treatment, ET-743 at 1.5 mg/m2 in 24 h continuous infusion every 21 days yielded an overall response rate close to 8% and stabilization rates of 30-40%, some lasting beyond 3 years. Leiomyosarcomas, liposarcomas, and synovial sarcomas may be the more sensitive histotypes. The major toxicities of ET-743 are hepatic--through biliary duct destruction--and hematologic. They are not cumulative and a significant number of patients may receive 12 courses or more. In a randomized Phase II study testing weekly ET-743 with treatment every 3 weeks, an improved progression-free survival rate was observed in the 3-weekly arm; the results of the follow-up Phase III trial should be available at the American Society of Clinical Oncology meeting of 2006. Phase I combination studies are in currently progress. ET-743 is a novel active drug for sarcoma which yields prolonged disease-free survival in subsets of patients.

Phase I and pharmacokinetics (PK) study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors

2029 Background: Trabectedin (ET-743) is a DNA minor-groove intercalating agent that blocks transcription factor activity, elicits G2/M cell cycle arrest, and induces apoptosis. Single agent activity has been demonstrated in soft tissue sarcoma (STS), breast, prostate and ovarian cancer. In preclinical studies sequential exposure of paclitaxel (P) followed by trabectedin (T) 24 hrs later resulted in synergy. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RD) of sequential P and T administered every 2 weeks in patients with advanced solid tumors. Methods: Escalating doses of P (80–120 mg/m2) over 1hr iv on day 1 and T ( 525–775 μg/m2) as 3 hrs iv day 2 every 2 weeks were administered. To evaluate drug:drug interactions, P was administered alone on day -7 in course 1 and PK studies performed courses 1 & 2. MTD was defined as ≥ 2/3 pts with dose limiting toxicity (DLT) in the 1st 2 courses. Results: 29 pts were enrolled and 27 were evaluable: median age was 48 yrs (19–82). M/F 16/13. Pts were treated over 5 dose levels: I 80/525 (n = 3), II 80/580 (n = 3), III 120/580 (n = 6), IV 120/650 (n = 11), V 120/775 (n = 4). A total of 213 courses of therapy were given, median number of course was 4 (range 1–28). There were 4 DLTs due to neutropenia delaying therapy > 1 week; one each at 120/580 (Grade 2) and 120/650 (Grade 4) and 2 at the MTD of 120/775 (Grade 4). Most common toxicities observed for P+T were neutropenia (24%), nausea (51%), vomiting (24%), transaminitis (23%), myalgia (24%) and alopecia (20%). One pt with PNET has an ongoing CR 16 months, one breast cancer pt (prior P failure) has PR 12 mo+ and 8 pts (6 STS) had SD > 3 mo (range 4–15 mo). There appear to be no marked drug:drug interactions for P and T. Preliminary non-compartmental PK results [geometric mean (CV%)] for T include t1/2 52.4 hr (43.6%); Cl l/hr/m2 31.6 (57.3%); Vss l/m2 1382 (69%) and for P are t1/2, 29.2 hr (39.1%); Cl l/hr/m2 15.3 (44.1%); Vss 213 l/m2 (72%). Conclusions: The recommended dose for this combination is paclitaxel 120 mg/m2 day 1 and trabectedin 650 μg/m2 day 2 administered every 2 weeks. Antitumor activity in STS and breast cancer, predictable PK parameters, and tolerable toxicity warrants further study of this combination. [Table: see text]

Phase II open label randomized study of trabectedin (T) given as two different dosing schedules in women with platinum-sensitive, recurrent ovarian carcinoma: Preliminary results

5031 Background: Trabectedin (Yondelis, ET-743) is a marine derived compound which binds to the minor groove of DNA distorting the DNA structure and induces apoptosis and cell cycle arrest. It has shown clinical activity in soft tissue sarcoma, ovarian, prostate and breast cancer. Methods: Patients (pts) with recurrent platinum sensitive ovarian carcinoma were randomized in a multicenter, open label study to receive T as 1.5 mg/m2 over 24 h infusion (schedule A) or 1.3 mg/m2 over 3 h infusion (schedule B) both every 3 weeks. All pts received dexamethasone premedication. Primary objective is to evaluate the response rate (RECIST) and secondary objectives are response duration, CA-125 response, time to progression and safety. Results: 107 pts were enrolled in 23 centers. Demographic and disease characteristics were well balanced. Toxicity and response data on the first 99 pts are available: median age 57 (25–78) years; ECOG PS=0: 72% and =1: 28%; pts received a median of 4 cycles (range:1–19 in A, 1–13 in B). Relative dose intensity was 84% and 93% respectively. Objective responses due to investigator’s assessment were 29% (8% CR, 21% PR) with 52% SD in A and 28% (11% CR, 17% PR) with 45% SD in B, with 11 pts not yet evaluable for response. CA 125 responses ≥ 50% occurred in 23% in A and 26% in B. TTP data will be presented. Safety: 501cycles were delivered; the most common any grade drug-related AEs per patient were (A and B) fatigue (56% and 47%), nausea (63% and 70%), vomiting (56% and 45%) and constipation (25% and 30%). Consistent with previous experience, alopecia, stomatitis and neurotoxicity were uncommon and mild/moderate. Grade 3/4 fatigue occurred in 15% in A and 4% in B. Grade 3/4 lab abnormalities were non-cumulative neutropenia (50% and 32%) and reversible ALT increase (58% and 53%). G-CSF support was not routinely given. There were 4 deaths <30 days last infusion date (3 in A unrelated to study drug, one in B due to related multiorgan failure). Conclusions: This analysis suggests that both T schedules appear active with manageable toxicity. There was a trend for less neutropenia and fatigue with schedule B. On the basis of these efficacy results, no additional phase III comparisons between these 2 schedules seem warranted [Table: see text]

Assessment of trabectedin (T) induced liver toxicity with correlation to liver morphology in a phase I study of T + pegylated liposomal doxorubicin (PLD)

9568 Background: T (ET-743) is a first-in-class compound that binds the minor groove of DNA. T has activity in soft tissue sarcoma and ovarian cancers with predictable, transient, non-cumulative and reversible hepatic toxicity, compatible with long term treatment. The combination of T and doxorubicin had preclinical synergistic activity. This study tested T + PLD in advanced malignancies. Methods: Eligibility included normal cardiac and liver functions, prior doxorubicin exposure <250 mg/m2. PLD 30 mg/m2 was administered iv 1-hour followed by 1 of 6 T doses (0.4 -1.3 mg/m2) iv 3 hours q 21 days. In select subjects (4 at pre/post cycle 1, 4 under long term treatment -cycle 14, 20, 30 and 30), liver biopsies were done with expert independent review. Results: Six dose levels of T were evaluated in 30 subjects. The DLTs were 1 grade 3 AST and 2 grade 4 ALT elevations seen at T 1.3 mg/m2. Grade 3–4 toxicities were: ALT elevation (4%), neutropenia (3%), hand-foot syndrome (2%), AST elevation (1%) and nausea/vomiting (1%). Liver biopsies were obtained from 8 subjects (1 in 0.6, 7 in 1.1 mg/m2 T dose cohorts), age 45–78 years, with sarcoma (4), and ovarian (2), uterine (1), and head and neck (1) cancers. T and PLD mean drug exposure for these subjects was 15 (2–36) and 12 (2–24) cycles, respectively. Mean total doses for T and PLD were 23.2 (3.4–39) and 597 (94–1296) mg, respectively. Findings included NASH (nonalcoholic steatohepatitis), severity ranging from minimal steatosis to moderate steatosis with fibrosis. Pre/post treatment biopsies showed no change in NASH pre/post in 3 cases, one subject had minimal post-treatment steatosis. No mitochondrial abnormalities or stellate cell activation were observed. Review concluded no evidence of persistent liver pathological abnormalities attributable to T. Conclusions: The MTD of T is 1.1 mg/m2 with 30 mg/m2 PLD q 21 days, and is well tolerated when both drugs are administered at near full therapeutic doses for prolonged periods. Liver biopsies did not demonstrate clinically relevant hepatic tissue toxicity. As reported previously, this is an active regimen which is being further evaluated in an ongoing Phase III study in relapsed ovarian cancer. [Table: see text]

Efficacy of a gemcitabine based multiagent chemotherapy regimen for advanced uterine sarcomas

15047 Background: Advanced stage uterine sarcomas (US) have poor prognosis. Active agents in US are doxorubicin, cisplatin and ifosfamide, with response rates (RR) of 25%, 19%, and 17% respectively. Given the poor response, there remains a need for other drugs. Gemcitabine has shown activity in soft tissue sarcomas. In trials with all subtypes of sarcomas, RR observed with single and multiagent schedules are ranging from 3 to 53%. There is scarce data on the use of gemcitabine in US. Aim of our study was to determine the clinical activity of gemcitabine based regimen in patients with US. Methods: From 2002–2005, data from11 chemotherapy naïve patients diagnosed with advanced stage US was reviewed who were receiving gemcitabine/ifosfomide/platinum (GIP) combination chemotherapy regimen in an adjuvant setting after TAH and surgical staging. Ifosfomide 2gm/m2 and Platinum 20 mg/m2 intravenously on days 1, 2 and 3. Gemcitabine 800 mg/m2 intravenously was administered on day 1 of a 28-day cycle. Results: Eleven pts were treated, all stages III and IV. The median age was 49 years. There were 6 carcinosarcomas, 4 LMS, and 1 ESS. Performance status was 0 (6 pts), 1 (5 pts). Four pts (36%) had undergone prior radiotherapy. The site of measurable disease in 10 pts (91%) was in the pelvis. The median number of GIP cycles received per pt was 6 (range 1–9). There were no treatment-related deaths. Hematologic toxicities of > Grade 3 were seen in 82% of pts and consisted of leukopenia and anemia. 36% of pts had an episode of febrile neutropenia. Neurotoxicty (Grade 3 in 2 pts), nausea (Grade 1/2 in 6 pts), and fatigue (Grade 1/2 in 7 pts) were observed. Three (27%) complete responses were observed, four pts had a partial response (36%), for an overall RR of 63%. Four pts had progression of disease (36%). Of the 7 pts demonstrating a response, 4 had previously been irradiated and 3 had not, such that the RR in those previously irradiated was 4/4 = 100% versus 3/7 = 43% in those not previously irradiated. Conclusions: The combination of GIP is well-tolerated and seems to be active in US, yielding RR higher than seen with single agent chemotherapy agents. Pts that received previous adjuvant radiation demonstrated the best responses to this regimen. A randomized trial is needed to evaluate the true value of this regimen in advanced stage US. No significant financial relationships to disclose.

Phase II Trial of Gemcitabine as First Line Chemotherapy in Patients With Metastatic or Unresectable Soft Tissue Sarcoma

The availability of effective chemotherapy agents or regimens for soft tissue sarcomas (STS) is limited. Response to available first line regimens is generally poor and response to second line regimens is rare. Considering the poor response of STS to available cytotoxic therapy, and the need to adequately evaluate the effectiveness of new agents, first line investigation of promising new agents is justified. Gemcitabine, a relatively new agent, has demonstrated effectiveness in several solid tumors. Limited clinical trials have suggested modest activity in STS. A multi-institutional study of gemcitabine in patients with STS, without prior chemotherapy for metastatic disease, was initiated in the Southwest Oncology Group May 1, 1998 and completed March 15, 1999. Patients were required to have metastatic or unresectable STS with no prior chemotherapy for metastatic disease. Gastrointestinal leiomyosarcomas and stromal tumors were not eligible. Patients were required to have a performance status of 0-2, measurable disease, adequate renal, hepatic, and hematologic function. The patients were given Gemcitabine 1000 mg/M2 iv over 30 minutes on days 1, 8, and 15, 22, 29, 36, 43, 57, 64, and 71. Dosage reduction was performed for cytopenias and/or other grade 3 or 4 toxicity. Forty-eight patients were registered to the study. The median age was 62 years (range, 30-80) with 21 male and 25 female patients. Two patients were ineligible (1 GI stromal tumor and 1 nerve sheath tumor). Forty-six patients are evaluable for response, toxicity, and survival. There were 2 treatment-related deaths (1 renal failure and 1 hemolytic uremic syndrome). Six additional patients experienced grade 4 toxicity (3 neutropenia, 2 dyspnea, 1 vomiting, and 1 renal failure). Three of the 46 eligible patients had a partial response (7%: 95% confidence interval 1-18%) and 8 patients had stable disease (20%). Nine patients had inadequate assessments to define response. Forty-five patients have died with a median survival of 6 months (95% confidence interval 5-10 months). Gemcitabine has minimal activity as a single agent at this dose and schedule in advanced STS. The low response rate does not justify further investigation of gemcitabine as a single agent in STS.

ET-743: A Novel Agent with Activity in Soft Tissue Sarcomas

Ecteinascidin-743 (ET-743) is a natural product derived from the marine tunicate Ectenascidia turbinate. ET-743 binds in the minor groove of DNA, blocks transcription factors activity, and traps protein from the nucleotide excision repair system, thus blocking cells in G2-M phase. ET-743 demonstrated cytotoxic activity at very low concentrations against sarcoma cell lines in pre-clinical studies. In several phase II clinical studies in patients with advanced sarcoma failing conventional doxorubicin- and ifosfamide-based chemotherapy, ET-743 delivered by continuous intravenous 24-hour infusion at a dose of 1,500 microg/m2 every 21 days yielded 8% overall response and 30%-40% stabilization rates for a clinical benefit rate close to 40%. Interestingly, long-term stabilizations over more than 3 years have been described. In vivo, ET-743 has a specific toxicity profile, the major toxicity of this product being hepatic, through biliary duct destruction, and hematologic. ET-743 has also been evaluated in first-line treatment for these patients. Finally, due to its original mode of action and the lack of cross-resistance with other chemotherapy agents, ET-743 was tested in a preclinical model in combination with other drugs. Synergy was reported in vitro with doxorubicin and cisplatin; phase I combination studies are in progress.

Ecteinascidin-743 (ET-743): Early Test or Effective Treatment in Soft Tissue Sarcomas?

Historically, phase II oncology studies have been used only for early screening, given that a control group is usually not used. Positive results in such single-arm studies are then followed by phase III studies to evaluate whether a new drug is a new standard of care. Sometimes, however, particularly in rare diseases for which randomized studies are difficult, two or more single-arm phase II studies may strongly suggest that a change in the standard of care is forthcoming. This issue of the Journal of Clinical Oncology includes such an example. In the late 1960s, extracts of the Caribbean marine tunicate Ecteinascidia turbinata were found to inhibit cell proliferation. However, it was not until the 1990s that the active compound, ecteinascidin-743 (ET-743; also known as trabectedin and Yondelis), was isolated, purified, and synthesized. Most likely, the compound is produced by the marine tunicate as a defense mechanism to survive in its natural environment. The cytotoxic effects of ET-743 seem to result from the selective alkylation in GC-rich regions of the minor groove of DNA. Although loss of mismatch repair does not affect the cytotoxicity of ET-743, lack of functional DNA-dependent protein kinase (involved in the DNA double-strand break repair pathway) leads to an increase in cytotoxicity. In preclinical studies, ET-743 was found to be particularly potent against a variety of soft tissue sarcoma cell lines, even those resistant to many other cytotoxic agents. The cytotoxicity of ET-743 was dose and time related (4 to 72 hours exposure). Cytotoxic concentrations of ET-743 produced an S/G2 block in all of the cell lines tested. All but one line had mutations in p53 and/or overexpressed the MDM2 protein and expressed the retinoblastoma protein. Because of its unique features, ET-743 was taken into clinical development, and activity in soft tissue sarcomas was suggested even in the phase I studies. Before formally testing the agent in this group of diseases, a pooled analysis from a phase I study and compassionate-use program reported that 14 of 25 patients with soft tissue sarcomas did not progress while on ET-743. Subsequently, a series of phase II studies were performed in patients failing prior chemotherapy. All studies have been using ET-743 at a dose of 1.5 mg/m as a 24-hour continuous infusion every 3 weeks. The European Organisation for Research and Treatment of Cancer (EORTC) studied ET-743 in 99 assessable patients who received a total of 410 cycles. There were eight partial responses (8%) and 45 patients with stable disease (44%), which lasted 6 months in 26% of the patients. Taken together, these results indicate a progression-arrest rate (partial response no change) of 53% (95% CI, 42% to 62%). The median duration of the time to progression was 105 days, and the 6-month progression-free survival rate was 29%. The median duration of survival was 9.2 months. In gastrointestinal stromal tumors, no activity was noted. Yovine et al treated 52 patients who were pretreated more heavily than those treated by the EORTC and received a median of three cycles (range, 1 to 20); 28% received six or more cycles. They observed two partial responses and 13 patients (25%) with stable disease, for a progression-arrest rate of 29% (95% CI, 17% to 43%). The 6-month progression-free survival rate was 24%. Median survival was 12.8 months, with 30% of patients alive at 2 years. Garcia-Carbonero et al treated 36 patients and observed one complete and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Unfortunately, the authors did not provide data on the number of patients with stable disease, but 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. In an ongoing randomized phase II study comparing a 3and 24-hour infusion of the same dose, progression-arrest rates ranged from 47% to 64%. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 24 AUGUST 2

Final results of a combination study between trabectedin and pegylated liposomal doxorubicin (PLD) in patients with advanced malignancies

3074 Background: Trabectedin (Yondelis, ET-743) is a marine-derived compound, which binds to the minor groove of DNA and is active at nM concentrations. Trabectedin is thought to act through the transcription-coupled nucleotide excision repair system. In clinical studies trabectedin has demonstrated activity in soft tissue sarcoma, ovarian and breast cancer. Methods: Eligibility criteria included normal liver function tests, limited prior doxorubicin exposure (≤ 250 mg/m2), and normal cardiac function. PLD 30 mg/m2 was administered i.v. over one hour followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) i.v. over 3 hours every 21 days. The effect of the combination on the liver morphology was evaluated in biopsies obtained from consenting patients. Results: Six dose levels of trabectedin were evaluated. The DLTs were one grade 3 AST and two grade 4 ALT elevations observed at a trabectedin dose of 1.3 mg/m2. The recommended dose is trabectedin 1.1 mg/m2 plus PLD 30 mg/m2. The thirty patients treated in this study were heavily pretreated: 23 had received 1–5 prior chemotherapies (median 3), 15 received prior radiotherapy, and 27 had prior tumor related surgery. Grade 3 and 4 toxicities in pooled cycles were: ALT elevation (4%), neutropenia (3%), hand-foot syndrome (2%), AST elevation (1%) and nausea/vomiting (1%). One subject terminated treatment after 6 cycles due to adverse events. Six patients had a partial response and 14 patients have had stable disease for > 3 months. Images of the liver morphology from patients treated with this drug combination will be presented. Conclusions: Trabectedin and PLD can be combined at near full single agent therapeutic doses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Johnson & Johnson