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Background: BET proteins are epigenetic readers and activators of oncogenic pathways in cancer. CC-95775 is a novel oral small molecule bromodomain inhibitor. It is a non-specific inhibitor with potent activity against all 4 BET family members (BRD2, BRD3, BRD4, BRDT), and shows additional activity towards several non-BET bromodomain proteins. Methods: CC-95775-ST-001 is a phase 1 dose-escalation study of CC-95775 in patients with advanced STs. Primary objectives were to determine safety and recommended phase 2 dose (RP2D). Secondary and exploratory objectives were pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity. Four dose levels (DLs), from 400 to 1200 mg, administered on 4 consecutive days (Day 1 to Day 4) followed by 24 days off, every four weeks (Q4W), were evaluated. Results: As of 16 Apr 2021, 24 evaluable patients were enrolled and treated. The RP2D was 1200 mg (300 mg on days 1-4 and 24 days off, Q4W). One patient treated at 800 mg and two at 1200 mg had dose-limiting toxicities: QT prolongation, left ventricular ejection fraction (LVEF) decreased and abnormal T wave. The most common treatment-related adverse event (TRAE) was thrombocytopenia in 11 patients (45.8%), 2 of them grade 3 (8.3%) and 1 grade 4 (4.2%). Safety profile consisted mainly of gastrointestinal and general disorders. Five patients (20.8%) had transient serious TRAEs: nausea, QT prolongation, abnormal T wave, posterior reversible encephalopathy syndrome and acute kidney injury. Eleven patients 11 (45.8) had disease stabilization, 9 of them with a duration of ≥ 16 weeks and 4 of them ≥ 24 weeks: melanoma, chondrosarcoma, adenoid cystic carcinoma and chordoma. Plasma exposures increased in a dose-proportional manner across DLs. Across all dose groups, median Tmax was between ~ 2-4 h post-dose, indicating rapid absorption. The terminal half-life was approximately 30 h and repeated dosing leads to drug accumulation, as expected: ~2 - 3 fold for AUC and Cmax. CC-95775 induced ≥50% decrease of the PD biomarker CCR1 at the 4-hour timepoint in the 1200 mg cohort. Conclusions: CC-95775 was well tolerated and showed preliminary antitumor activity in heavily pretreated patients with advanced malignancies. The RP2D was 1200 mg Q4W. The favorable PD profile improved tolerability and enabled less frequent dosing. Further evaluation of CC-95775 alone or in combination in STs is warranted. Citation Format: Thierry Lesimple, María José de Miguel, Cristophe Le Tourneau, Mariano Ponz-Sarvise, Marie Paule Sablin, Diego Salas Benito, Bishoy Hanna, Henry Chang, Xin Wei, Marta Ocejo Garcia, Pilar Lardelli, Tania Sánchez, Josep Lluís Parra Palau, Zariana Nikolova, Emiliano Calvo. CC-95775, a reversible, oral bromodomain and extra-terminal (BET) inhibitor in patients with advanced solid tumors (STs): Results of a phase 1 study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P033.

Background Preclinical and clinical data suggest that xeroderma pigmentosum G gene (XPG) status might predict trabectedin efficacy. This phase 2 study evaluated the efficacy of trabectedin at a dose of 1.3 mg/m 2 as a 3-hour intravenous infusion every 3 weeks in hormone receptor–positive, HER-2 (human epidermal growth factor receptor 2)-negative, advanced breast cancer patients according to the tumor level of XPG mRNA expression. Patients and Methods Patients were stratified into high-XPG (>3) or low-XPG (≤ 3) groups. The primary efficacy end point was progression-free survival (PFS) rate at 16 weeks (PFS4); secondary efficacy end points were overall response rate (ORR), duration of response, PFS, overall survival, and safety of trabectedin in this patient population. Results Forty-four patients were treated, 21 with high XPG and 23 with low XPG. Four high-XPG and 6 low-XPG patients experienced PFS4; the criterion for further recruitment (> 6 patients experienced PFS4) was thus not met, and recruitment was stopped. One high-XPG patient had a partial response (ORR, 5%). One low-XPG patient had a complete response, and 2 low-XPG patients had partial responses (ORR, 13%). Comparison of efficacy parameters between high-XPG and low-XPG patients showed no statistically significant differences. ORR in the efficacy population was 9.3%, median PFS was 1.9 months, and overall survival was 11.8 months. The safety of trabectedin in breast carcinoma was similar to that shown in other indications. Conclusion Trabectedin as single agent had limited activity in hormone-positive, HER-2–negative advanced breast cancer. XPG mRNA expression was not predictive of trabectedin efficacy.

Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m(2) intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype.

Introduction: BCMA is a tumor necrosis factor (TNF) receptor superfamily transmembrane glycoprotein essential for the maturation and survival of plasma cells. CC-93269 is an asymmetric 2-arm humanized IgG TCE that binds bivalently to BCMA and monovalently to CD3ε in a 2+1 format (Seckinger A, et al. Cancer Cell. 2017;31:396-410). The CC-93269-mediated interaction between T cells and BCMA-expressing myeloma cells induces T cell receptor/CD3 crosslinking leading to T cell activation, and release of proinflammatory cytokines and cytolytic enzymes, resulting in myeloma cell death. In preclinical studies with CC-93269 and related molecules, 2+1 BCMA TCEs induced tumor regression in animal models and promoted myeloma cell death in primary pt myeloma cells. Here we report interim results from a phase 1 dose-finding study (CC-93269-MM-001; NCT03486067) evaluating CC-93269 in pts with RRMM. Methods: Eligible pts had RRMM and had received ≥ 3 prior regimens without prior BCMA-directed therapy. In dose escalation, CC-93269 was administered intravenously over 2 hours on Days 1, 8, 15, and 22 for Cycles 1-3; Days 1 and 15 for Cycles 4-6; and on Day 1 for Cycle 7 and beyond, all in 28-day cycles. Dose escalation involved 2 stages: in stage 1, CC-93269 was given in fixed doses; in stage 2, pts received a fixed first dose on Cycle 1 Day 1, followed by intrapatient dose escalation on Cycle 1 Day 8. Primary objectives were to assess the safety and tolerability of CC-93269 and define the maximum tolerated dose (MTD), non-tolerated dose (NTD), and/or recommended phase 2 dose (RP2D). Minimal residual disease (MRD) was assessed after clinical response in pt bone marrow aspirate samples by Next Generation Flow using the EuroFlow panel. MRD negativity was reported only if a minimum sensitivity of < 1 tumor cell in 105 nucleated cells was achieved. Results: As of May 24, 2019, 19 pts had received CC-93269. Median age was 64 years (range 51-78), with a median of 6.2 years (range 1.4-13.9) since initial diagnosis. The median number of prior regimens was 6 (range 3-12) and included treatment with autologous stem cell transplantation (73.7%), allogenic stem cell transplantation (10.5%), lenalidomide (100%), pomalidomide (84.2%), bortezomib (100%), carfilzomib (84.2%), and daratumumab (DARA; 94.7%). All pts had MM refractory to their last line of therapy, with 16 (88.9%) refractory to DARA, 17 (89.5%) to their last proteasome inhibitor, and 16 (84.2%) to their last immunomodulatory agent. CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.6 weeks (range 1.6-32.0) with pts receiving a median of 4 cycles (range 1-8). Grade 3-4 treatment-emergent adverse events were reported in 15 (78.9%) pts and included 10 (52.6%) pts with neutropenia, 8 (42.1%) with anemia, 5 (26.3%) with infections, and 4 (21.1%) with thrombocytopenia. No pt required dose modifications. Cytokine release syndrome (CRS) was reported in 17 (89.5%) pts, the majority of whom reported a maximum grade 1 (n = 11 [57.9%]) or grade 2 (n = 5 [26.3%]), and occurred most frequently with the first or second dose (n = 22 of 27 events [81.5%]). CRS prophylaxis was implemented with dexamethasone for first dose and dose increases in pts receiving ≥ 6 mg. Of 27 CRS events, 8 (29.6%) were managed with dexamethasone and 10 (37.0%) with tocilizumab. One pt receiving 6 mg CC-93269 as first dose and 10 mg on Cycle 1 Day 8 died on study in the setting of CRS, with a potential infection as a contributing factor. Dose-related pharmacodynamic activity, including peripheral blood immune cell redistribution and transient release of pro- and anti-inflammatory cytokines, was observed in pts. Of the 12 pts treated with ≥ 6 mg CC-93269 in Cycle 1, 10 pts achieved a partial response (PR) or better (overall response rate; 83.3%), including 7 (58.3%) with a very good partial response (VGPR) or better and 4 (33.3%) with a stringent complete response (sCR) (Table); 9 (75.0%) pts achieved MRD negativity. The median time to response was 4.2 weeks (range 4.0-13.1), and 10 of 10 responses were ongoing with follow-up ranging from 2.1 to 4.7 months. The NTD, MTD, and RP2D have not yet been reached. Conclusions: CC-93269, a 2+1 BCMA TCE, shows a manageable safety profile and promising efficacy, including MRD-negative sCRs, in pts with heavily pretreated RRMM. The study continues to enroll in the dose escalation phase. Updated safety and efficacy data will be presented at the meeting. Disclosures Costa: Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Karyopharm: Consultancy; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. Wong:Genentech: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding; Fortis: Research Funding; Juno: Research Funding. Bermúdez:MSD: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Fresenius: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Mateos:Pharmamar: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ocio:BMS: Honoraria; Sanofi: Research Funding; Mundipharma: Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Novartis: Consultancy, Honoraria; AbbVie: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Rodríguez-Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Li:Celgene Corporation: Employment, Equity Ownership. Sarmiento:Celgene Corporation: Employment. Lardelli:Celgene Corporation: Employment, Equity Ownership. Gaudy:Celgene Corporation: Employment, Equity Ownership. Boss:Celgene Corporation: Employment, Equity Ownership. Kelly:Celgene Corporation: Employment. Burgess:University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain; Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant.

Ewing sarcoma is a rare connective tissue tumor characterized by the translocation of the EWS gene, mainly between chromosome 11 and 22, giving rise to gene re-arrangements between the EWS gene and various members of the ETS gene family. Multi-agent chemotherapy has improved the outcome for patients with localized Ewing sarcoma, but survival of patients with recurrent/metastatic disease remains poor. An exploratory two-stage, single-arm Phase II multicenter trial of the synthetic alkaloid, PM00104, was conducted in patients with recurrent Ewing sarcoma. The primary end point of the trial was objective response rate. PM00104 was administered at a dose of 2 mg/m(2) on Days 1, 8 and 15 of a 4 week cycle. Seventeen patients were recruited. No objective responses were reported in the 16 patients evaluable for efficacy. Recruitment was closed without proceeding to the second stage of the trial. Four patients achieved stable disease as best response, and in two of these patients the stabilization was longer than 4 months. The median progression-free survival was 1.8 months (95 % CI, 0.9-3.5 months) and median overall survival was not reached (95%CI, 56.2 % at censored data). Pharmacokinetics in patients with Ewing sarcoma was similar to that previously reported in other patient populations. PM00104 showed modest activity in Ewing sarcoma at 2 mg/m(2) on a weekly schedule. There remains an unmet need for effective therapies for patients with advanced/metastatic Ewing sarcoma.

The aim of this phase I study was to identify a feasible dose and schedule for the combination of cisplatin and trabectedin. The regimen evaluated consisted of cisplatin at a fixed dose of 75 mg/m(2) 1-hour intravenous (i.v.) infusion followed by escalating doses of trabectedin 3-hour i.v. infusion, both administered on day 1 every 3 weeks (q3wks). Two dose-limiting toxicities (DLTs), grade 4 neutropenia longer than 7 days duration and grade 3 vomiting despite standard antiemetic therapy, occurred at the starting dose of trabectedin (0.75 mg/m(2)). The immediately lower dose (trabectedin 0.60 mg/m(2)) was evaluated in a total of 8 patients; no DLTs occurred and this was declared the recommended dose (RD). The safety profile of the combination at this dose and schedule was consistent with the known side effects of each agent alone: nausea, fatigue, transient transaminase elevations and neutropenia. No new or unexpected adverse reactions were observed. Two partial responses were reported at the RD in patients with pretreated ovarian cancer. Comparison with population pharmacokinetic data suggests a PK interaction between trabectedin and cisplatin leading to increased plasma exposure of trabectedin in the first 48 h, lower platinum clearance and longer half-life. In conclusion, although the trabectedin dose achieved with this combination was low (50 % of single-agent when given q3wks), this day 1 q3wks trabectedin plus cisplatin combination showed a feasible administration, a tolerable safety profile and some antitumor activity.

Purpose This analysis determined the incidence of serious rhabdomyolysis events reported during trabectedin treatment since the first phase I clinical trial in April 1996 up to September 2010. Methods Search was done in the Yondelis® Pharmacovigilance and Clinical Trials databases using a list of terms according to the Medical Dictionary for Regulatory Activities (MedDRA, v. 13.1), followed by a medical review of all cases retrieved. Total estimated sample was 10,841 patients: 2,789 from clinical trials; 3,926 from compassionate use programs; and 4,126 treated in the marketplace. Two groups were identified: (1) rhabdomyolysis and (2) clinically relevant creatine phosphokinase (CPK) increases without acute renal failure (ARF). Descriptive analysis included demographic, clinical/laboratory data, and contributing/confounding factors. Potential predictive factors were evaluated by multivariate stepwise logistic regression analysis. Possible changes of pharmacokinetics (PK) in patients with rhabdomyolysis were explored using a population PK model. Results The global incidence of rhabdomyolysis was 0.7 %, and most cases occurred in Cycle 2 of treatment. The incidence of fatal cases was 0.3 %. None of the variables evaluated to detect potential risk factors of rhabdomyolysis were predictive. Additionally, CPK increases (without ARF) were detected in 0.4 % of patients as an incidental finding with good prognosis. Conclusions Rhabdomyolysis is an uncommon event during trabectedin treatment. Multivariate analyses did not show any potential factor that could be predictive or represent a significantly higher risk of developing rhabdomyolysis. Nevertheless, close patient monitoring and adherence to drug administration guidelines may help to limit the incidence of this event.

International audience; AIMS: Approximately 20% of soft tissue sarcomas (STS) have subtype-specific chromosomal translocations; these generate chimeric oncoproteins which can act as abnormal transcription factors. Since trabectedin can bind to DNA and displace transcription factors, antitumour activity was explored in translocation-related sarcoma (TRS) subtypes. METHODS: The current retrospective pooled analysis includes data from 81 patients with TRS treated in 8 phase II trials. RESULTS: TRS subtypes were: synovial sarcoma (SS, n=45), myxoid-round cell liposarcoma (MRC-L-sarcoma, n=27), alveolar soft part sarcoma (ASPS, n=4), endometrial stromal sarcoma (ESS, n=3) and clear cell sarcoma (CCS, n=2). All but one patient had received prior chemotherapy (median of 2 lines). Patients received a median of 4 trabectedin cycles (range, 1-48; median dose intensity=0.40 mg/m(2)/week). Partial responses according to Response Evaluation Criteria in Solid Tumours (RECIST) occurred in 8 patients (ORR=10%; 95% CI, 4-19%): four in MRC-L-sarcoma; three in SS and one in ESS. Tumour control rate (ORR plus stable disease) was 59% (95% CI, 48-70%). Median PFS was 4.1 months (6-month PFS rate=40%). Median overall survival was 17.4 months (survival rate at 12 months=60%). Trabectedin had a manageable safety profile. CONCLUSION: Trabectedin demonstrates encouraging disease control in TRS. Since these promising results were generally noted in patients following chemotherapy, a phase III randomised trial in first-line is ongoing to compare trabectedin with doxorubicin-based chemotherapy in patients with TRS.

This analysis provides a cross-study evaluation of the cardiac safety of trabectedin.Drug-related cardiac adverse events (CAEs) were retrieved from phase I-III clinical trials, pharmacovigilance databases, and spontaneously reported cases. Left ventricular ejection fraction (LVEF) was monitored in combination phase I studies with doxorubicin or pegylated liposomal doxorubicin (PLD) and in a phase III trial (with PLD).CAEs [grade 4 cardiac arrest with severe pancytopenia and sepsis (n = 1 patient), grade 4 atrial fibrillation (n = 2), and grade 1 tachycardia (n = 1)] occurred in 4/283 patients (1.4%) in 6 single-agent phase I trials. CAEs (grade 1 sinus tachycardia in a hypertensive patient and grade 1 ventricular dysfunction) occurred in 2/155 patients (1.3%) in 4 phase I combination trials. Results from 19 single-agent phase II trials showed CAEs in 20/1,132 patients (1.8%): arrhythmias (tachycardia/palpitations; n = 13; 1.1%) were the most common. A rather similar rate of symptomatic CAEs was observed in both arms of a phase III trial in recurrent ovarian cancer: 6/330 patients (1.8%; PLD) and 11/333 patients (3.3%; trabectedin/PLD). No clinically relevant LVEF changes occurred in phase I combination trials. In the phase III trial, LVEF decreases from baseline were similar: 9% of patients (PLD) and 7% (trabectedin/PLD), with no relevant symptoms. During postmarketing experience in soft tissue sarcoma (2,046 patients treated), 4 CAEs (2 cardiac arrest, 2 cardiac failure; ~0.2%) occurred in patients with preexisting conditions.Trabectedin has a low incidence of CAEs, consisting mainly of arrhythmias. This extensive data review indicates a low cardiac risk profile for trabectedin.

11519Background: Patients (pts) with relapsed Ewing sarcoma (ES) have a poor outcome. New therapeutic agents are needed. L is a new anticancer drug that blocks transcription and induces DNA double-...

8570Background: SCLC is a deadly cancer and despite initial 80% response, almost all patients (pts) will relapse and die of this disease. Limited options exist after failure of first line, with a m...

574 Background: BRCA 1/2-associated breast cancer share homologous recombination deficiency, but also have independent and potentially actionable roles. Novel drugs with innovative mechanism of action, lacking cross-resistance with other used agents are needed for BRCA 1/2 MBC. Trabectedin (TR) and its analog, lurbinectedin (L), have shown to be active in BRCA 1/2 MBC. This study was sought to determine if there was a difference in activity of these agents between BRCA1 and 2 carriers. Methods: Safety and efficacy in MBC BRCA 1/2 were analyzed in 2 separate phase II trials of single agent TR and L. Results: 88 patients were evaluated: 34 with TR, 54 with L. Median age: 46 and 43, respectively. Median (range) prior chemotherapy lines: TR, 4 (1-10); L, 2 (0-5). Clinical responses were seen in the 2 trials (see table) and were higher in BRCA2 than in BRCA1 (33% vs 9% with TR and 61% vs 26% with L). Main adverse event was myelosuppression (grade 3-4 neutropenia / thrombocytopenia / febrile neutropenia: TR, 62.1%/24.3%/10.8% L, 66.7%/20.4%/20.4%). Non-hematological toxicity was mostly grade 1-2: fatigue, nausea/vomiting and high transaminases (grade 3/4 TR, 40.5%, L 18.5%). Conclusions: Remarkable activity of trabectedin and lurbinectedin as single agents was observed in BRCA 2 associated MBC. This finding warrants further investigation. One potential mechanistic rationale is the role of both lurbinectedin and BRCA 2 in transcription. Safety was acceptable and manageable in both studies. Clinical trial information: NCT01525589. [Table: see text]

5586 Background: Lurbinectedin (L) is a new anticancer drug that blocks trans-activated transcription, induces DNA double-strand breaks and modulates the tumor microenvironment. Advanced endometrial cancer (EC) is an unmet medical need. Methods: Activity in EC patients was reviewed in 3 trials: a phase IB study of lurbinectedin combined with doxorubicin (L+DOX), a phase I study of PM combined with paclitaxel (L+TAX) and a phase II single-agent basket trial (L). Baseline characteristics, safety and efficacy were analyzed. Results: 97 patients were evaluated: 34 (2 cohorts) with L+DOX, 11 with L+TAX and 52 with L. Median age was similar in the 3 studies. Endometrioid was the most frequent histology. Median (range) of prior chemotherapy lines for advanced disease was: L+DOX, 1(0-2); L+TAX, 2(1-3); L, 1(0-2). Responses were observed in the 3 studies (see table). Main adverse event was myelosuppression (grade 3-4 neutropenia/thrombocytopenia/febrile neutropenia: L+DOX Cohort A, 94%/26%/40%; L+DOX Cohort B, 79%/10%/16%; L+TAX, 54%/0%/0%; L, 33%/6%/6%). Non-hematological toxicity was mostly grade 1-2: fatigue, nausea and vomiting, and transaminase increase. Conclusions: Lurbinectedin is active as single agent and in combination in patients with advanced EC, with remarkable activity in terms of response rate, duration of response and PFS when combined with doxorubicin. Safety was acceptable in L+DOX Cohort B, L+TAX and L, and myelosuppression was well managed. Clinical trial information: NCT01970540. [Table: see text]

Background Breast cancer is a heterogeneous disease defined by both germline and somatic abnormalities. In preclinical models, tumors carrying homologous recombination defects are highly sensitive to trabectedin. This phase II trial evaluated the efficacy and safety of trabectedin in BRCA1/2 germline mutation carriers with pretreated metastatic breast cancer (MBC). Patients and methods Trabectedin 1.3 mg/m2 as a 3-h i.v. infusion was administered every 3 weeks until progression or intolerance. The primary efficacy end point was the objective response rate (ORR) as per RECIST. Secondary efficacy end points comprised time-to-event end points, and changes in tumor volume and expression of tumor marker CA15.3. Safety was evaluated using the NCI-CTCAE. Results Forty BRCA1/2 germline mutation carriers with MBC were included. Confirmed partial response (PR) occurred in 6 of 35 assessable patients [ORR = 17%; 95% confidence interval (CI) 7% to 34%] and lasted 1.4–6.8 months. Median PFS was 3.9 months (95% CI 1.6–5.5 months). Eight patients (21%) showed changes in tumor volume, and 14 (40%) a clinical benefit. Trabectedin-related adverse events were generally mild/moderate, the most common being fatigue, nausea, constipation and anorexia. Severe laboratory abnormalities (neutropenia, transaminase increases) were mostly transient and noncumulative, and were managed by dose adjustments. Conclusions With the caveat of the limited patient number, trabectedin monotherapy showed activity and was well tolerated in heavily pretreated MBC patients selected for germline BRCA mutation. These results prompt further evaluation of trabectedin alone or combined with other specific drugs in this indication. ClinicalTrials.gov NCT00580112.

Objective. Trabectedin in combination with PLD improves progression-free suivival (PFS) and overall response rate (ORR) in comparison to PLD alone in patients with relapsed ovarian cancer (J Clin Oncol; 2010 28:3107-14). Here we report the impact of the treatment combination on patient-reported functional status and symptoms. Methods. Patient-reported outcome (PRO) questionnaires, EORTC-QLQ C30, OV28, and EQ-5D were completed by patients at screening and on Day 1 of every other treatment cycle starting with Cycle 1, and at the end-of-treatment visit. Results. Of the 672 patients randomized in this study, 663 treated patients completed at least one of the baseline questionnaires. Median cycles of treatment was 6 (131 days) for the combination arm and 5 (143 days) for the monotherapy arm. Longitudinal data analyses showed no significant differences between the treatment arms for any of the pre-specified scales. Similar analyses of other scales, including Health Index scores and Health State on the Visual Analog Scale, support these findings. Start of subsequent therapy was significantly delayed in the combination arm compared with the monotherapy arm (p = 0.0032). Conclusions. The addition of trabectedin to PLD led to little or no decrement in patient-reported functional status and symptoms in patients with relapsed ovarian cancer, as compared to treatment with PLD alone. The combination led to manageable and non-cumulative overall toxicity with a fewer PLD-associated adverse events, and a significant improvement in PFS and ORR compared to single agent. (C) 2012 Elsevier Inc. All rights reserved.

Background Previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin. This exploratory phase II trial evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment. Methods Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cutoff: XPG = 0.99, ERCC1 = 3.47 and BRCA1 = 12.00. Trabectedin was administered as a 1.3 mg/m2 3-hour intravenous infusion every 3 weeks (q3wk). The primary efficacy endpoint was the progression-free survival rate at 3 months. Objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was a secondary efficacy endpoint. Results Two of 18 evaluable patients (11.1%; 95% CI, 1.38–34.7%) achieved progression-free survival rate at 3 months. The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was early finalized. No objective responses per RECIST were achieved. Four patients had stable disease. Median PFS was 1.3 months, and median overall survival was 5.9 months. Trabectedin was usually well tolerated, with a safety profile similar to that described in patients with other tumor types. Conclusions Customized treatment with trabectedin 1.3 mg/m2 3-h q3wk according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLC patients pretreated with platinum. Therefore, further clinical trials with trabectedin as single agent in this indication are not warranted.

Aims To determine the maximum tolerated dose, the recommended dose (RD) for phase II studies, dose-limiting toxicities and pharmacokinetics (PK) for plitidepsin administered as a 3-h intravenous infusion every 2 weeks (one cycle) to children with refractory or relapsed solid tumours. Methods Consecutive cohorts of patients were treated according to a standard ‘3 + 3’ design with escalating doses of plitidepsin at 4, 5 and 6 mg/m2. Additional 15 patients were recruited at the RD to further evaluate safety and pharmacokinetic associations with respect to age, dose level and toxicity. Results Thirty-eight of 41 patients registered received plitidepsin. Dose-limiting toxicities during the first three treatment cycles related to myalgia, elevated creatine phosphokinase, transaminase increase and nausea/vomiting. The RD for plitidepsin is 5 mg/m2. PK analyses revealed high inter-patient variability in plasma, but a similar clearance of plitidepsin in children and adolescents. One partial response confirmed at 4 weeks in a patient with neuroblastoma and one unconfirmed partial response in a pancreatoblastoma were observed; four other patients with neuroblastoma, medulloblastoma, glioblastoma and rhabdoid tumour had disease stabilisations lasting ⩾3 months. Conclusion Plitidepsin administered to children as a 3-h infusion every 2 weeks is received with manageable toxicity for children with cancer, and the RD is 5 mg/m2. Pharmacokinetic parameters in children and adolescents are comparable to adults. Future phase II studies of plitidepsin are warranted, and our results suggest that plitidepsin could be appropriately developed in combination with other antitumour where myelosuppression is dose-limiting.

This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC).Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP).Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase.Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.

Background To evaluate neoadjuvant trabectedin (1.5 mg/m2 24-h i.v. infusion every 3 weeks; three to six cycles) in patients with locally advanced myoxid liposarcoma (ML) previously untreated with chemotherapy or radiation. Patients and methods Primary efficacy end point was pathological complete response (pCR) or tumoral regression rate. Objective response according to RECIST (v.1.0) was a secondary end point. Results Three of 23 assessable patients had pCR [13%; 95% confidence interval (CI), 3% to 34%]. Furthermore, very good and moderate histological responses were observed in another 2 and 10 patients, respectively. Histological decrement in the cellular and vascular tumor component and maturation of tumor cells to lipoblasts were observed in both myoxid and myoxid/round cell variants. Seven patients had partial response according to RECIST (objective response rate of 24%; 95% CI, 10% to 44%). No disease progression was reported. Neoadjuvant trabectedin was usually well tolerated, with a safety profile similar to that described in patients with soft tissue sarcoma or other tumor types. Conclusion Trabectedin 1.5 mg/m2 given as a 24-h i.v. infusion every 3 weeks is a therapeutic option in the neoadjuvant setting of ML.

The objective of this study was to evaluate the antitumor activity and safety profile of 5 mg/m2 plitidepsin administered as a 3-h continuous intravenous infusion every 2 weeks to patients with advanced malignant melanoma who relapsed or progressed after one line of systemic therapy. Objective response rate (primary efficacy endpoint) was evaluated according to Response Evaluation Criteria In Solid Tumors and toxicity was assessed using National Cancer Institute -Common Toxicity Criteria Version 2.0. Of 39 enrolled patients (median age: 53 years), 37 patients were treated who received a total of 167 treatment cycles (median: 3 cycles per patient; range: 1-32). All patients had received prior systemic therapy with a median of one line per patient (range: 1-6 lines). Of the 35 evaluable patients, two dacarbazine-resistant patients (5.7%) with metastatic cutaneous melanoma achieved partial responses. Five other patients (14.3%) reported stable disease (median stable disease duration: 3.5 months; range: 2.2-15.8 months). Therefore, the rate of tumor growth control was 20.0%. With a median follow-up of 11.0 months, the median progression-free survival was 1.3 months and the median overall survival was 3.5 months. Six patients (16.2%) had the following treatment-related grade 3/4 adverse events: myalgia (n = 3), injection-site reaction (n = 2), hypersensitivity, hypotension, and fatigue (n = 1 each). One patient was withdrawn from the trial because of grade 4 hypersensitivity reaction and hypotension. No severe neutropenia was reported. Plitidepsin showed a minor degree of antitumor activity in patients with refractory advanced malignant melanoma. Further evaluation of plitidepsin in combination schedules may be warranted.

TPS2604 Background: PM01183 (lurbinectedin) is a new anticancer drug that binds to the DNA minor groove and blocks trans-activated transcription, inducing formation of double-strand DNA breaks lead...

TPS652 Background: Hormone receptor-positive, HER2-negative breast cancer (BC) is currently associated with 3-4 years overall survival in the metastatic setting and, after ≥2 relapses, therapeutic approaches are reduced. XPG expression is frequently modified in BC. T is a cytotoxic agent that forms a complex with the XPG, inducing cell apoptosis. As a single agent, T has shown anti-tumor activity in patients with poor prognosis BC, and a better response to T in BC patients with XPG RNA overexpression has been observed. Methods: This is an open-label, phase II study of T (1.3 mg/m2 in 3-hour intravenous infusion every 3 weeks) in patients with hormone receptor-positive, HER2-negative advanced BC, according to their primary tumor’s XPG expression. Primary endpoint: to evaluate the efficacy of T in terms of progression free survival rate at 4 months (PFS4) according to the patient’s XPG expression. Secondary endpoints: Comparison of PFS, overall response rate, duration of response, overall survival and safety profile in XPG-high and XPG-low patients. Assignment: BC patients who have previously received anthracyclins and/or taxanes and who progressed after 2-5 chemotherapy lines will be assigned according to their XPG expression from paraffin embedded tumor samples to stratum A (XPG-high [>3]) or to stratum B (XPG-low [≤3]) (threshold was selected from median XPG expression values observed in a previous trial). Statistical methods: A two-stage design was chosen: at a first stage 20 patients will be enrolled in each stratum. A futility analysis (O’Brien Fleming boundary) based on the primary endpoint (PFS4) will be conducted once 40 evaluable patients have been recruited. If ≥ 7 out of 20 patients achieve PFS4, recruitment will continue to a maximum sample size of 50 evaluable patients per stratum. If ≥ 22 out of 50 patients achieve PFS4, T will be considered active in this group (alpha error: 0.025, power: 80%). To date, 35 patients (16 XPG-high and 15 XPG-low) have been enrolled from three countries and five centers. Recruitment is ongoing.

1125 Background: Single-agent T has shown antitumor activity in pts with pretreated MBC. Preclinical data suggested T displays increased activity in cell lines having intact nucleotide excision repair (NER), evidenced in particular by XPG expression or homologous recombination repair (HRR) deficient MBC. Final results of the multicenter phase II trial of T in metastatic breast cancer patients are presented. Methods: T was given at 1.3 mg/m2 as a 3-hour intravenous infusion every three weeks, to pts with pretreated progressive MBC. Group A: triple negative (TN); Group B: HER-2 overexpressed (HER-2+); and Group C: BRCA1/2 mutation carriers. Endpoints were objective response rate by RECIST per independent radiological review, duration of response, progression free survival (PFS), safety and pharmacogenomics. Results: A total of 122 pts (median [med] age 51; ECOG 0/1, 49/51%) were enrolled (A: 50, B: 37, C: 35). For all groups, med number of prior chemotherapy regimens was 3 (1–9) and med number of T cycles a...

2517 Background: T is a synthetic compound originally derived from the marine organism Ecteinascidia turbinata with a mechanism of action based on DNA binding and involving the transcription-depend...

1038 Background: Single agent T has shown activity in soft tissue sarcoma (STS), ovarian, and breast carcinoma. The European Commission has approved T for STS treatment in adults after failure of standard therapy and for platinum sensitive relapsed ovarian cancer. In 3 phase II studies T showed antitumor activity in pts with pretreated MBC. Preclinical and clinical data suggested T may display specific activity among certain nucleotide excision repair (NER) intact or homologous recombination repair (HRR) deficient MBC, and prompted this phase II trial. Methods: T was given at 1.3 mg/m2 as a 3-hour iv infusion 3qwks to pts with pretreated progressive MBC: Group A: ER/PR/HER2- negative; Group B: HER2 overexpressed (3+), and Group C: BRCA1/2 mutation carriers. Endpoints were objective response rate by RECIST, duration of response, progression free survival (PFS), safety, and pharmacogenomics (PGx). Results: Group A was closed due to low response rate; results have already been presented. A total of 55 pts ha...

e13599 Background: Plitidepsin (Aplidin, APL) is a cyclic depsipeptide of marine origin in phase II/III development in cancer patients (pts). It induces apoptosis through rapid and sustained JNK ac...

2568 Background: PM00104 is a novel synthetic alkaloid related to the marine compounds jorumycin and renieramycins. Preliminary preclinical studies suggest changes in cell cycle and DNA binding properties and transcriptional inhibition as main mechanisms of action. PM00104 has shown broad in vitro and in vivo anti-tumor activity (IC50 ≤ 10-8 M) with an acceptable toxicology profile. Methods: The aim of this phase I study was to assess the safety profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK), relationship between PK and pharmacodynamics (PD) and anti-tumor activity of PM00104 administered as a 24-hour i.v. infusion q3w. Sequential cohorts of 3–6 pts were treated at 133, 266, 400, 800, 900, 1600, 3200, 4000 and 5000 μg/m2. Results: Twenty nine pts have been treated (18 male, 11 female; median age: 59, range: 44–78; ECOG PS ≤2). Five pts developed DLTs: 2 pts at 5000 μg/m2 (grade 4 thrombocytopenia/neutropenia and grade 3 nausea/vomiting in 1 pt; and grade 3 nausea in 1 pt); 1 at 4000 μg/m2 (grade 4 neutropenia/thrombocytopenia and grade 3 asthenia); 1 at 3200 μg/m2 (grade 3 tumor pain) and 1 at 266 μg/m2 (grade 3 transaminase increase). The MTD was reached at 5000 μg/m2 and the RD at 4000 μg/m2. At the RD 6 more pts have been included in order to further evaluate the safety profile and anti-tumor activity. Other adverse events included nausea and vomiting (more frequent at doses ≥800 μg/m2), fatigue, anorexia and diarrhea; most of them being of ≤grade 2 severity. No objective responses were seen but 3 pts with pancreatic adenocarcinoma, hepatocarcinoma and lower esophagus adenocarcinoma presented stable disease lasting >3 months. PM00104 shows a dose-proportional PK profile, the half-life being 20–30 hours and the volume of distribution around 1000 L. Conclusions: PM00104 has shown an acceptable safety profile with signs of anti-tumor activity in pts with advanced malignancies when administered as a 24-hour i.v. infusion q3w. PM00104 is also being evaluated with other administration schedules as monotherapy and in combination with other anti-tumor agents. [Table: see text]

10525 Background: Trabectedin (ET-743, Yondelis), a marine-derived alkaloid has demonstrated significant activity in the treatment of soft tissue sarcomas (STS) in phase III trials, and has recently received EMEA approval in this indication. A subtype that accounts for 10% of STS, MRCL, displays the fusion FUS-CHOP in 95% of all cases. Preliminary results of neoadjuvant trabectedin (T) in advanced MRCL show reduction in the radiological density of the tumor, clinical improvement, and a pathological complete response (pCR) in the resected tumor mass. A phase II study to further determine the response to T in the MRCL population is presented. Methods: In this multicenter Phase II trial, patients (pts) with locally advanced (stage III) or locally recurrent MRCL were treated for 3 - 6 cycles with T (1.5 mg/m2 q3wk) in the neoadjuvant setting. Main endpoints were: pCR rate, objective response rate by RECIST, and correlation of molecular parameters from tissue samples with clinical outcomes. Results: Twenty-five pts with locally advanced MRCL have been recruited, of whom 20 are evaluable. All had the translocation (t12q13, 16p11) which causes the chimeric FUS-CHOP. Median age was 53 (23–75) and male:female ratio was 1. Thirteen pts completed therapy and underwent curative surgery. Pathological assessment was performed in 10 pts: 2 achieved pCR, 1 as per central pathology review and 1 by local pathology assessment. In addition, 1 pt had a very good pathological response. Ten patients remain to be histologically evaluated. Response rate by RECIST from pts who completed therapy was: 6 partial responses (46%) and 7 disease stabilizations. Remarkably, pathological response does not entirely correlate with response by RECIST since the pts with pCR still had radiological disease but no malignant component was found in the excised tumor mass (only connective and reactive tissue). Two serious adverse reactions of severe rhabdomyolysis, and asthenia, nausea and transaminase elevation were reported. Most common toxicities were liver enzyme elevation, neutropenia and thrombocytopenia. Conclusions: These preliminary results in terms of objective and complete pathologic responses, strongly suggest that T may have a role in the neoadjuvant setting in pts with MRCL. [Table: see text]

10028 Background: Plitidepsin (Aplidin) is a cyclic depsipeptide isolated from the tunicate Aplidium albicans, nowadays manufactured by synthesis. It is a rapid and potent inductor of apoptosis. Ph...

Diffuse intermediately differentiated lymphocytic lymphoma (IDL) is a rare (approximately 2.5%) histologic subtype of malignant lymphoma. We have reviewed the morphologic, immunophenotypic, and clinical features of this disease in 23 patients treated at the National Cancer Institute in the 25-year period between 1963 and 1988. These tumors are uniformly of B-cell origin, but most of them express the T-cell antigen CD5; lambda light chain was expressed nearly twice as frequently as kappa. Median age at diagnosis was 58 years; all patients presented with stage III or IV disease, and the natural history of disease in these patients was heterogeneous. Median survival of patients was more than 5 years, but those with liver involvement documented by biopsy had a significantly shorter survival. No other prognostic factor or combination of prognostic factors significantly affected survival in this small series; however, patients with high expression of the proliferation-associated nuclear antigen Ki-67, absence of cell-surface antigens CD9 and CD10, and blastic morphology appeared to have poorer survival. Treatment was heterogeneous, but patients who achieved a complete response to combination chemotherapy survived longer than patients who failed to achieve a complete response. Only two patients had complete responses lasting longer than 2 years. Unlike patients with follicular lymphoma, those with relapsed IDL did not undergo histologic progression of the disease to an aggressive lymphoma. However, as with patients with follicular lymphoma, it was possible to observe patients with IDL without therapy for periods up to 5 years. Although a significant minority of patients may have very aggressive disease, it appears that, in most patients, IDL behaves similarly to other lymphomas with indolent histology, and thus, an optimal therapeutic approach has not yet been defined.

Aim This randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS). Methods Patients were randomly assigned (1:1) to receive trabectedin 1.5mg/m 2 24-h intravenous (i.v.) infusion every 3weeks (q3wk) ( Arm A ), or doxorubicin 75mg/m 2 i.v. q3wk, or doxorubicin 60mg/m 2 i.v. plus ifosfamide (range, 6–9g/m 2 ) i.v. q3wk ( Arm B ). Progression-free survival (PFS) by independent review was the primary efficacy end-point. Results One hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p =0.9573; hazard ratio=0.86, p =0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm. Conclusion Neither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.

TPS10101 Background: One third of sarcoma histotypes have specific chromosomal translocations which result in abnormal transcription factors, integral to the change to a malignant phenotype. T is the first of a new class of anti-tumor agents with a transcription-targeted mechanism of action. In vitro evidence exists of the ability of T to interfere with the aberrant transcription factor’s binding to DNA promoters in TRS. Patients with TRS, such as myxoid/round cell liposarcomas (MRCL) have benefited from long-lasting tumor control in response to T. Methods: A randomized, phase III study of T (1.5 mg/m2 in 24-h intravenous infusion every 3 weeks [q3wk]) vs doxorubicin 75 mg/m2 q3wk, or doxorubicin 60 mg/m2 with ifosfamide 6-9 g/m2 q3wk) as first line treatment in patients with advanced TRS. Primary aim: to determine the efficacy of T vs doxorubicin-based therapy by comparing progression-free survival (PFS) in each arm. Secondary aims: comparison of PFS rates at six months, response rate (RR), PFS and RR by histological type (MRCL vs other subtypes), overall survival, safety, exploratory response evaluation by Choi criteria and pharmacogenomic analyses. Patients with confirmed TRS of the following subtypes: MRCL, alveolar soft part sarcoma,angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid sarcoma,myxoid chondrosarcoma and synovial sarcoma, are stratified by performance status (PS 0 vs 1-2) and sarcoma subtype (MRCL vs other subtypes) and randomized (1:1 ratio) to T or doxorubicin ± ifosfamide. Confirmation of the translocation by fluorescence in situ hybridization is compulsory for inclusion in the primary efficacy analysis. An adaptive design was chosen to test the reduction in relative risk of progression or death with T, an interim analysis will be conducted with 45 PFS events from 80 evaluable patients. To date 117 patients have been enrolled from six countries and 29 centers. An independent data monitoring committee met on 15 November 2011 and concluded that the trial should continue as planned.

e16540 Background: Trabectedin is an originally marine-derived antineoplastic agent, currently produced by chemical synthesis. In early phase II trials, trabectedin showed antitumor activity as a s...