Pretreated Soft Tissue Sarcoma Research Articles

Single-agent temozolomide as salvage therapy in heavily pretreated metastatic sarcoma patients.

Treatment options for patients with metastatic sarcoma are limited. The goal of this study was to investigate the effectiveness of temozolomide in pretreated patients with soft tissue sarcoma. We recorded the pathological, clinical, and treatment data of the patients with metastatic soft tissue sarcoma retrospectively. We evaluated the efficacy and side effects of temozolomide in this patient group. This study involved 16 patients. The average age was detected as 48 (21-73) years. Six (37.5%) patients had de-novo metastatic disease at diagnosis. Primary of tumors had originated from intra-abdominal (43.7%), extremity (31.3%), head-and-neck (12.5%), and intrathoracic (12.5%) regions. The patients previously had received at least two different chemotherapy regimens (75%), pazopanib (50%) and palliative radiotherapy (31.3%). Temozolomide-related median progression-free survival time was found as 3.5 (95% CI, 2.6-4.3) months. One patient (6.3%) had a partial response, while four patients (25%) had stable disease. Nine individuals (56.3%) had grade 1-2 adverse events, while one patient (6.3%) had grade 3-4 adverse events. We observed that temozolomide was well tolerated but had limited efficacy in the treatment of metastatic sarcoma patients. In patients with extensively pretreated soft tissue sarcoma, temozolomide may be considered a therapeutic option as a single-agent.

Efficacy of temozolomide in pretreated patients with metastatic sarcoma.

e23550 Background: Sarcoma is a rare heterogeneous group malignancy and most commonly arises from soft tissue. The primary treatment modality is surgery. However, in metastatic disease, treatment options are limited. Cytotoxic chemotherapy is preferred for palliative treatment. This study aimed to assess the efficacy of temozolomide in heavily pretreated soft tissue sarcoma. Methods: We evaluated the patients with a metastatic various types of soft tissue sarcoma retrospectively. The patients with gastrointestinal stromal tumors and bone sarcomas were excluded from the study. We recorded the clinical, pathological, and treatment data of the patients. SPSS 25v was used for statistical analysis. Survival analysis was performed with the Kaplan-Meier method. Results: Sixteen patients were included in this study. The median age was 48 (range, 21-73) years. Six (37.5%) patients were de-novo metastatic. Tumor localizations were intra-abdominal (43.8%), extremity (31.2%), intrathoracic (12.5%), and head-and-neck (12.5%). The most common metastatic sites were lung (75%), bone (31.8%), liver (18.8%), respectively. For metastatic disease, the patients received at least two different chemotherapy regimens (75%), pazopanib (50%) and palliative radiotherapy (31.3%). Metastasectomy was also performed on five (31.3%) patients. Median progression-free survival was 3.5 (95% CI, 2.6-4.3) months. Partial response was observed in one (6.3%) patients, stable disease in four (25 %) patients. Eleven (68.8%) patients had progressive disease. Grade 1-2 adverse events were observed in nine (56.3%) patients, grade 3-4 in one (6.3%) patients. Conclusions: We showed that temozolomide was well-tolerated but had a limited efficacy for the treatment of patients with metastatic sarcoma. Treatment options for metastatic sarcomas are limited. Temozolomide may be considered a treatment option in patients with heavily pretreated soft tissue sarcoma.

Bispecific NKG2D-CD3 and NKG2D-CD16 Fusion Proteins as Novel Treatment Option in Advanced Soft Tissue Sarcomas.

Soft tissue sarcoma (STS) constitutes a rare group of heterogeneous malignancies. Effective treatment options for most subtypes of STS are still limited. As a result, especially in metastatic disease, prognosis is still dismal. The ligands for the activating immunoreceptor NKG2D (NKG2DL) are commonly expressed in STS, but generally absent in healthy tissues. This provides the rationale for utilization of NKG2DL as targets for immunotherapeutic approaches. We here report on the preclinical characterization of bispecific fusion proteins (BFP) consisting of the extracellular domain of the NKG2D receptor fused to Fab-fragments directed against CD3 (NKG2D-CD3) or CD16 (NKG2D-CD16) for treatment of STS. After characterization of NKG2DL expression patterns on various STS cell lines, we demonstrated that both NKG2D-CD16 and NKG2D-CD3 induce profound T and NK cell reactivity as revealed by analysis of activation, degranulation and secretion of IFNγ as well as granule associated proteins, resulting in potent target cell lysis. In addition, the stimulatory capacity of the constructs to induce T and NK cell activation was analyzed in heavily pretreated STS patients and found to be comparable to healthy donors. Our results emphasize the potential of NKG2D-CD3 and NKG2D-CD16 BFP to target STS even in an advanced disease.

Efficacy of Pazopanib With or Without Gemcitabine in Patients With Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma

Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required. To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone. This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020. Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B). The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates. A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological. This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma). German Clinical Trials Identifier: DRKS00003139.

LBA67 TRAMUNE, a phase Ib study combining trabectedin and durvalumab, results of the expansion cohort in patients with advanced pretreated soft tissue sarcomas

Trabectedin (T) activity is partly mediated by targeting tumor associated macrophages. We report results of a multicenter phase Ib study assessing safety and preliminary efficacy of T combined with the PDL1 inhibitor durvalumab (D) in patients (pts) with unresectable or metastatic STS and relapsed OC, focusing on the STS expansion cohort.

Activity of regorafenib in advanced pretreated soft tissue sarcoma

Regorafenib, a multitargeted tyrosine kinase inhibitor, proved to be active in patients with soft tissue sarcomas (STS). We conducted an open-label, non-randomized, single-center phase II study in advanced pretreated STS patients. Patients received regorafenib 160 mg daily on days 1 enrule 21 of a 28-day cycle. The primary endpoint was the progression-free survival (PFS) at 8 weeks. Toxicity was registered. Between April 2015 and November 2016, 21 patients were enrolled in the trial. A total of 13 out of 21 evaluable patients (61.9%) were progression-free at 8 weeks. Median PFS was 3.8 months (95% CI: 2.1-9.4). Median overall survival was 14.8 months (95% CI: 7.7-27.8). In the intention-to-treat population, we reported a PFS of 66.7% at 3 months (95% CI: 40.4-83.4) and 16.7% at 12 months (95% CI: 4.1-36.5). As per the RECIST criteria, the response rate was 4.7% (1 partial response out of 21 evaluable patients) with a clinical benefit rate of 61.9%; no complete response was observed. Treatment was well tolerated. Regorafenib shows signs of clinical activity in patients with advanced STS. ClinicalTrials.gov NCT02307500.

Apatinib for patients (pts) with advanced soft tissue sarcoma (STS) after chemotherapy: A prospective, open-label, single-arm, multicentered study.

11553 Background: The development of STS therapeutics has been challenging, especially patients who failed chemotherapy. Anti-angiogenesis inhibitors had shown activity in STS, Apatinib is a TKI targeting on VEGFR-2 which has shown activity in many solid tumors. Methods: A Phase II, open-label, Single-arm, multicentered study was conducted in previously treated pts with advanced STS in China. The patients received apatinib 500mg orally qd in a 28-day-cycle, until disease progression or unacceptable adverse events. Antitumor response assessment was performed every 8 weeks per RECIST V1.1. The primary endpoint was PFS rate in 6 months and secondary endpoint was ORR and OS. Results: As cut-off on Jan 20th 2019, a total of 53 patients were enrolled in 9 centers, 51 patients received at least 2 cycles of Apatinib, 1 patient is still in treatment. The main histological subtypes were alveolar soft part sarcoma(n = 11), synovial sarcoma(n = 6), leiomyosarcoma (n = 6), clear cell sarcoma(n = 6) and undifferentiated pleomorphic sarcoma(n = 5). Overall, 27 of 51 patients were progression free at six months and the 6-m PFS rate was 53.32% (95%CI 37.76%, 66.63%). Until final follow-up, the ORR was 18.75% (9/48) and DCR was 87.5% (42/48). Additionally, median PFS was 7.13 (95%CI 3.84, 9.23) months and median OS has reached up to 24.67 (9.30-NE) months. Adverse events (AEs) were detected among all pts, hypertension and proteinuria are the most common AEs, occurred in 84.91% and 73.57% pts respectively. Grade 3/4 related adverse events were detected in 86.79% of pts, Grade 3/4 hypertension was the most common grade3/4 AE (56.60%). Conclusions: Overall, the present study demonstrates that apatinib has a clinically meaningful anti-tumor activity in pretreated STS pts, showing durable responses and prolonged overall survival. Some of the pts had a long-time benefit from the treatment. Apatinib was safe and generally well tolerated. Further studies on specific STS subtypes would be meaningful. Clinical trial information: NCT03064243 .

A randomized phase II study of durvalumab and tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma (MEDISARC, AIO-STS 0415).

TPS11075 Background: Soft tissue sarcomas (STS) are rare tumors and exhibit substantial histological diversity. Efficacious targeted 1st line treatment for advanced or metastatic STS is not available, and the standard therapy has been anthracycline-based for decades. This strategy shows poor efficacy, as demonstrated by a median Overall Survival (OS) of 12-20 months. Several STS subtypes, however, have been shown to express PD-L1, and immune checkpoint inhibitors (ICI) have demonstrated principle anti-tumor activity in pretreated STS. Our ongoing clinical trial tests the activity and safety of ICI combination therapy in the first-line setting. We hypothesize that the dual checkpoint blockade with Durvalumab (PD-L1) and Tremelimumab (CTLA-4) improves overall survival in STS when compared to the standard of care doxorubicin. Methods: MEDISARC is a multi-center phase II trial that is enrolling adult treatment-naïve patients with histologically confirmed STS of intermediate or high grade (FNCLCC grade 2 or 3) not amenable to surgery with curative intent and ECOG performance status 0-2. Chemosensitive histologic STS are eligible. 100 patients will be randomized 1:1, stratified by ECOG status (0 vs. 1/2). Patients in the experimental arm are treated with fixed doses of durvalumab (1.5 g Q4W) and tremelimumab (75 mg Q4W for 3 cycles, then Q12W) until Progressive Disease (PD) or for a maximum of 12 months. Doxorubicin treatment in the standard arm is at 75 mg/m2 Q3W and limited to 6 cycles. OS is the primary endpoint. Secondary endpoints include 2-year OS rate, PFS, ORR according to conventional and modified RECIST 1.1, safety and tolerability and health-related quality of life (EORTC QLQ-C30). OS analysis may be performed when the required number of events (E=70) has been observed. All randomized and treated subjects will be included in the efficacy and safety analysis. The accompanying translational research aims to identify prognostic and predictive biomarkers in blood and tumor tissue. Enrollment of patients started in April 2018 and is ongoing. As of February 2019, 32 patients have been enrolled. The study is sponsored by AIO-Studien-gGmbH, Berlin, Germany. Clinical trial information: 2016-004750-15.

Results of a prospective randomized phase III T-SAR trial comparing trabectedin (T) vs best supportive care (BSC) in patients with pretreated advanced soft tissue sarcoma (ASTS): A French Sarcoma Group (FSG) trial.

11508Background: With the exception of a study in translocation-related STS (Kawai, 2015), T has never been compared to BSC in a study including patients (pts) with all sarcoma histotypes. The effi...

Managing pazopanib toxicity in the treatment of advanced soft tissue sarcoma

Background Pazopanib is a multikinase inhibitor registered for the treatment of advanced renal clear cell carcinoma (RCC) and as second or further-line therapy in advanced non-adipocytic soft tissue sarcoma (STS). It is a relatively well-tolerated compound, but, as with many other tyrosine kinase inhibitors (TKI), chronic toxicity may become a challenge that both patient and physician need to take into account when starting treatment. This retrospective study investigated toxicities and their management in STS patients treated with pazopanib in routine clinical practice in Italy. Materials and Methods Data were collected between January 2013 and May 2016 at Candiolo Cancer Institute and Prato Medical Oncology Unit. The primary objective was to describe observed toxicities in a real-life setting, and use this information to inform strategies for adverse event management. Results A total of 43 patients with advanced STS who received treatment with pazopanib were included. Median progression-free survival was 4 months and median overall survival was 18 months. The most common toxicities were fatigue (74.4%), hypertension (72%), hair hypopigmentation (74.4%) and diarrhea (60.5%). Liver toxicities occurred in less than one-third of patients. Severe adverse events, requiring drug interruption, were relatively rare. Conclusions This study confirms the safety and efficacy of pazopanib in pretreated unresectable or metastatic soft tissue sarcoma, and highlights the importance of close follow-up and patient support to improve compliance and treatment duration.

ISY-13-4 - Clinical trials of trabectedin for soft tissue sarcoma

Doxorubicin and ifosfamide are the two main effective therapies for STS, but few therapeutic options exist after those two therapies.Trabectedin, a marine-derived anti-tumor agent, exerts its anti-tumor activity by inhibiting DNA repair through its binding to the DNA minor groove, and it also inhibits transcription factors derived from fusion proteins. It is effective for soft tissue sarcomas (STS), especially translocation-related sarcomas (TRS).Pooled analysis from five phase II studies of trabectedin (n = 350, pre-treated in 91%) showed 10% response rate, 28.3% disease-control rate, and OS of 13-14 months.In a randomized phase III study comparing trabectedin or dacarbazine (2:1) for pts with advanced liposarcoma or leiomyosarcoma pretreated with anthracycline and other cytotoxic drug (n = 518), trabectedin showed improvement in PFS (HR 0.55, 4.2M vs 1.5M), but did not show improvement in OS (HR 0.87). Most common Grade 3-4 adverse events were myelosuppression and transient elevation of transaminases.In Japan, randomized open label phase II study comparing trabectedin 1.2mg/m2 versus best supportive care in pts with TRS unresponsive or intolerant to standard chemotherapy, trabectedin showed improvement of PFS (HR 0.07, 5.6M versus 0.9M). Common adverse events were nausea, decreased appetite, decreased neutrophil, increased ALT, common and adverse events of G3 or more were neutrophil decreased (67%), ALT increased (61%), febrile neutropenia (14%). G4 rhabdomyolysis were also seen (3%).From these data, trabectedin was approved for STS in Japan at 2015 and should be considered as a therapeutic option for pretreated STS, especially TRS. Doxorubicin and ifosfamide are the two main effective therapies for STS, but few therapeutic options exist after those two therapies. Trabectedin, a marine-derived anti-tumor agent, exerts its anti-tumor activity by inhibiting DNA repair through its binding to the DNA minor groove, and it also inhibits transcription factors derived from fusion proteins. It is effective for soft tissue sarcomas (STS), especially translocation-related sarcomas (TRS). Pooled analysis from five phase II studies of trabectedin (n = 350, pre-treated in 91%) showed 10% response rate, 28.3% disease-control rate, and OS of 13-14 months. In a randomized phase III study comparing trabectedin or dacarbazine (2:1) for pts with advanced liposarcoma or leiomyosarcoma pretreated with anthracycline and other cytotoxic drug (n = 518), trabectedin showed improvement in PFS (HR 0.55, 4.2M vs 1.5M), but did not show improvement in OS (HR 0.87). Most common Grade 3-4 adverse events were myelosuppression and transient elevation of transaminases. In Japan, randomized open label phase II study comparing trabectedin 1.2mg/m2 versus best supportive care in pts with TRS unresponsive or intolerant to standard chemotherapy, trabectedin showed improvement of PFS (HR 0.07, 5.6M versus 0.9M). Common adverse events were nausea, decreased appetite, decreased neutrophil, increased ALT, common and adverse events of G3 or more were neutrophil decreased (67%), ALT increased (61%), febrile neutropenia (14%). G4 rhabdomyolysis were also seen (3%). From these data, trabectedin was approved for STS in Japan at 2015 and should be considered as a therapeutic option for pretreated STS, especially TRS.

Salvage Therapy in Advanced Adult Soft Tissue Sarcoma: A Systematic Review and Meta-Analysis of Randomized Trials.

Prognosis for patients with metastatic soft tissue sarcomas (STS) is dismal, with median overall survival (OS) of 8-12 months. The role of second-line therapy has been inconsistently investigated over the last 20 years. This systematic review and meta-analysis was performed to assess the efficacy of salvage treatment in pretreated adult type STS, gastrointestinal stromal tumor (GIST) excluded. PubMed, Web of Science, SCOPUS, EMBASE, CINAHL, and The Cochrane Library were searched for randomized phase II/phase III trials exploring second- or beyond therapy lines in pretreated metastatic STS. Two independent investigators extracted data; the quality of eligible studies was resolved by consensus. Hazard ratio (HR) of death and progression (OS and progression-free survival [PFS]) and odds ratio (OR) for response rate (RR) were pooled in a fixed- or random-effects model according to heterogeneity. Study quality was assessed with the Cochrane's risk of bias tool, and publication bias with funnel plots. Overall, 10 randomized trials were selected. The pooled HR for death was 0.81 (95% confidence interval [CI] 0.73-0.9). Second-line therapy reduced the risk of progression by 49% (HR = 0.51, 95% CI 0.34-0.76). This translated into an absolute benefit in OS and PFS by 3.3 and 1.6 months, respectively. Finally, RR with new agents or chemotherapy doublets translated from 4.3% to 7.6% (OR = 1.78, 95% CI 1.22-2.50). Better survival is achieved in patients treated with salvage therapies (chemotherapy, as single or multiple agents or targeted biological agents). A 3-months gain in OS and an almost double RR is observed. Second lines also attained a reduction by 50% the risk of progression. There is some evidence that salvage therapies after first-line failure are able to improve outcome in metastatic soft tissue sarcoma (STS). Trabectedin, gemcitabine-based therapy, and pazopanib are currently approved drugs used after conventional upfront treatment. This meta-analysis reviews the benefit of new agents used in randomized trials in comparison with no active treatments or older agents for recurrent/progressed STS. The results show that modern drugs confer a statistically significant 3-month benefit in terms of overall survival, and an increase in response rate. Despite a limited improvement in outcome, currently approved second-line therapy should be offered to patients with good performance status.

Evaluation of response after neoadjuvant treatment in soft tissue sarcomas; the European Organization for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group (EORTC–STBSG) recommendations for pathological examination and reporting

At present, there is not a commonly used and generally accepted standardized approach for the pathologic evaluation of pretreated soft tissue sarcomas. Also, it is still unclear whether the cut-off for prognostic relevance is similar in the many different histological subtypes of STS. This manuscript, produced by a European Organization for Research and Treatment of Cancer – Soft Tissue and Bone Sarcoma Group (EORTC–STBSG) endorsed task force, aims to propose standardization of the pathological examination process and the reporting of STS resection specimens after neoadjuvant radio- and/or chemotherapy.

Trabectedin for Advanced Soft Tissue Sarcomas: A Single Institution Experience

We retrospectively analyzed data from patients who had been treated with trabectedin at our institution between April 2009 and August 2011. Data from 25 patients with recurrent soft tissue sarcoma (leiomyosarcoma: n = 8; liposarcoma: n = 5) were used to assess the efficacy and safety of trabectedin 1.5 mg/m(2) given every 3 weeks. Most patients (n = 14) had been heavily pretreated with ≥ 2 previous chemotherapy lines. Eight (32%) patients achieved a partial response according to dimensional and tumor density changes, and seven (28%) patients had stable disease for ≥ 3 months (clinical benefit rate = 60%; n = 15). Median progression-free survival was 6.4 months and overall survival 19.3 months. Common adverse events were fatigue, nausea, anemia and transient transaminase increases. Treatment with trabectedin is effective and well tolerated in heavily pretreated soft tissue sarcoma patients. Tapering dexamethasone courses and switching trabectedin administration to an every 4 weeks schedule effectively dealt with persistent fatigue without compromising effectiveness.

Sorafenib in advanced, heavily pretreated patients with soft tissue sarcomas

Therapeutic options for patients with advanced pretreated soft tissue sarcomas are limited. However, in this setting, sorafenib has shown promising results. We reviewed the data of 33 patients with soft tissue sarcoma treated with sorafenib within a named patient program in Austria. Twelve physicians from eight different hospitals provided records for the analysis of data. Among the 33 patients, the predominant histological subtype of sarcoma was leiomyosarcoma (n=18, 55%). Other subtypes were represented by only one or two cases. Fifteen patients presented with metastases at the time of diagnosis. Another 17 patients developed metastases later in the course of the disease (data on one patient are missing). Most of the 33 patients had undergone resection of the primary (n=29, 88%) and half of the patients had received radiotherapy (n=17, 52%). Chemotherapy for metastatic disease had been administered to 30 patients (91%). The majority had received two or more regimens of chemotherapy (n=25, 76%) before sorafenib treatment. The use of sorafenib resulted in a median time to treatment failure of 92 days in patients with leiomyosarcoma and 45 days in patients with other histological subtypes. One-third of the patients derived benefits from treatment: four patients were documented with partial response and six with stabilized disease. In terms of treatment-related toxicity, skin problems of various degrees and gastrointestinal disturbances were frequently reported. In this retrospective analysis of heavily pretreated patients with advanced soft tissue sarcomas, sorafenib was associated with some antitumor activity and an acceptable toxicity profile.

A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group

Background:Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS.Methods:We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate.Results:Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21–79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10–35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months.Conclusion:Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.

Phase II trial of ifosfamide in combination with sorafenib in patients with advanced soft tissue sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study.

10523 Background: Recent studies suggest that VEGFR inhibition could play a role in the treatment of soft tissue sarcoma (STS). Prior studies by our group showed that the combination of ifosfamide with sorafenib resulted in preclinical additive activity and that was feasible and safe in the phase I trial. Methods: Patients (pts) with advanced STS, previously treated with doxorubicin, no prior ifosfamide, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this multicenter phase II study, receiving sorafenib 400 mg bid po continuously and ifosfamide 2 g/m2 iv for 3 days together with mesna 400 mg/m2 every 3 weeks. The primary endpoint was progression-free rate (PFR) at 3 months. A one-sample binomial design was used (PFR P0=40%, P1=60%, α=0.10, β=0.20), requiring at least 19 of 35 pts free of progression at 3 months to be considered positive. Results: From September 09 to March 12, 35 pts were enrolled at 11 centers. Median age was 55 (18-73). PS: 0-13, 1-18; 2-4 pts. Histologic types were: LMS 12, Lipo 6, SS 5, MPNST 2, other 10 pts. . The median number of cycles administered per patient was 4. PFR at 3 months was 67%, with 23 pts being free of progression at 3 months. Median progression-free survival was 4.8 months (95% CI, 1.9-6.3) and median overall survival was 16.2 months. PR was achieved in 17% pts. Most common grade 3-4 toxicities were asthenia (25%), hand-foot syndrome (11%) and neutropenia (20%) resulting in 3 episodes of neutropenic fever. Other common toxicities (G1-4) included emesis (34%), rash (22%), diarrhea (34%), hypertension (11%) and mucositis (9%). Conclusions: The combination of ifosfamide and sorafenib is active and has acceptable toxicity in pts with doxorubicin pretreated STS. The PFR at 3 months might exceed the expected with ifosfamide alone warranting further investigation. Clinical trial information: EudraCT: 2007-002176-34.

Efficacy and tolerability of trabectedin in heavily pretreated soft tissue sarcomas (STS).

e20513 Background: Advanced STS have a dismal prognosis with a median overall survival of 1 year, reported in most phase III clinical trials. Although newer targeted therapies are currently being evaluated, chemotherapy continues to be the mainstay of treatment. However, due to the limited activity of current treatments, new therapies are needed. Trabectedin, an alkylating agent to the minor groove of DNA, has demonstrated significant activity after failure of anthracyclines and ifosfamide. Methods: This is a retrospective analysis of 22 patients diagnosed with advanced, heavily pretreated STS, treated with trabectedin in a single institution. From 06/ 2000 to 06/ 2011, trabectedin was administered as a 3-hour infusion every 21 days at a dose of 1.1-1.5mg/m2 with steroid premedication. No patients were excluded from this analysis. Results: Median age was 53 years (range 21-82). The most frequent histologic subtypes were: 27% liposarcomas, 18% leiomyosarcomas, 13% malignant fibrous histiocytomas and 9% synovial sarcomas. One third of patients had received 3 or more prior therapy lines. Overall response rate was 8.33% and stable disease (more than 16 weeks) was achieved in 36.3% of patients (75% of liposarcomas and 50% of leiomiosarcomas). The median duration of response was 11 weeks (range 4-22). Dose reduction was required in two patients, but no patient discontinued treatment due to drug-related toxicity. There were no treatment-related deaths. The most relevant toxicity was grade 3/4 neutropenia in 25% of patients (one case of febrile neutropenia). Grade 3/4 transaminitis was observed in the only patient who received trabectedin with doxorubicin for one cycle, and continued with trabectedin monotherapy without further liver function test disturbances. A case of transient rhabdomyolysis was observed; the patient had mild renal dysfunction and liver metastases, but recovered completely. Grade 1/2 nausea, vomiting and asthenia were reported in 8.33%, 4.17% and 45.83% of patients, respectively. Conclusions: Trabectedin achieves significant clinical benefit in heavily pretreated advanced STS patients. Trabectedin was well tolerated with reversible and manageable toxicity, demonstrating an acceptable safety profile.

A phase I study of MDM2 antagonist RG7112 in patients (pts) with relapsed/refractory solid tumors.

e13600^ Background: RG7112 is a small molecule MDM2 antagonist, designed to non-genotoxically activate p53. A phase I dose escalation (DE) was performed, followed by a sarcoma biomarker extension (EXT) in pts with wild type TP53. Methods: 106 pts (58M, 48 F), median age 57.9 yrs (range 22-84) participated; 76 in 9 cohorts (DE) from 20 to 1800 mg/m2, orally QD x 10 q28 days. 30 pts with sarcoma were treated at MTD (2500 mg) (EXT) with pre-and on dose (d5+/-2) biopsies. Analyses included TP53 mutation (AmpliChip), MDM2 amplification (ISH), p53 and p21 IHC, MDM2 RT-PCR, Ki-67, TUNEL and [18F]-FLT-PET. Blood was obtained for PK and MIC-1, a PD marker of p53 activation. Results: DE: MTD was1440 mg/m2/d (2500 mg flat dose). PK was ~dose linear (t½ 1-1.5 d) with high variability (CV~70%) in AUC and Cmax . Adverse events included nausea/GI and exposure-related neutropenia/thrombocytopenia. 3 DLTs: diarrhea, pancytopenia, hyponatremia occurred (at ≥ 640 mg/m2). Evidence of activity included: 1) concentration dependent increase in plasma MIC-1 (% baseline), 2) decrease in [18F]-FLT PET and PR each in liposarcoma pts at 1800 mg/m2 and 1440 mg/m2, respectively. EXT: Grade3/ 4 cytopenias at MTD precluded subsequent cycles in 6/8 pts (10 day schedule). Dosing was changed to 5 days, and only 3 patients had Gr3/4 cytopenias. 8/22 pts remained on study for >4 cycles, including 2 pts with SD for 7 and 9 cycles respectively. 3 of 4 EXT pts had decreased [18F]-FLT-PET activity. Biopsies (pre- and on treatment) demonstrated: 1) increase in p53 (median 1.5 fold change (X) by IHC, n=15); 2) increase in p21 (median 2.7X by IHC, n=14); 3) increase in MDM2 (median 2.5X by RT-PCR, n = 27); 4) decrease in % Ki-67(+) cells (median % change from baseline -65.4%, range -91% to +275%, n=17 ); 5) increase in TUNEL(+) cells of 9.0 (density of + cells/mm2, range -26.2 to +45.5, n=22). These results were seen both in tumors with and without MDM2 gene amplification, and in multiple sarcoma subtypes. Conclusions: RG7112 has manageable AEs (GI ) and cytopenias correlating with AUC. Single agent disease control, and biomarker activity was seen in both MDM2 amplified and non-amplified, heavily pretreated soft tissue sarcoma pts, with changes reflecting activation of p53-related pathways.

Efficacy and safety of panobinostat (LBH-589), a histone-deacetylase inhibitor (HDACi), in patients (pts) with advanced, previously treated soft tissue sarcoma (STS) and sex cord tumors (SCT): A study from the French Sarcoma Group.

10027 Background: Treatment options are limited for pts with advanced pretreated STS. HDACi have shown activity in preclinical models of STS and SCT Methods: Pts with advanced pretreated STS and SCT were enrolled in this open label, single arm, multicenter phase II study. Panobinostat was given orally, 40 mg thrice per week. The primary end-point was 3-month progression-free rate according to RECIST 1.1 using central review. Fleming-A’Hern single-stage design for phase II trials was used, and assuming a type I error alpha of 5% with 90% power, 15/47 pts were needed to be progression free at 3 months to reject a rate of 20%. Results: Fifty three pts were enrolled between January 2010 and January 2011. Median age was 59 (range 21-79) years, and 22 (42%) pts were males, 13 had translocation-related sarcoma (TRS) and 4 had SCT. All but 5 pts had metastatic disease. The most common sites were the lung and the liver. All but one pt had documented disease progression prior to study entry. The median number of prior lines of therapy was 2 (range 1-7). Panobinostat dose was lowered to 20 mg thrice a week after 11 pts were enrolled based on the recommendation of an independent safety committee. Fifty-two pts were evaluable for toxicity (1 pt never received treatment), 48 pts (92%) reported at least one adverse event (AE) and 22 (42%) reported at least one treatment-related grade 3 or 4 AE. The most common grade 3/4 AEs were thrombocytopenia, fatigue and anemia. Fifty pts were evaluable for the primary end-point, of these, 12 pts (24%, 95%CI[13-38%]) were progression-free at 3 months, including 4/13 pts (31%, 95%CI[9-61%]) with TRS and 2/4 pts (50%, 95%CI[7-93%]) with SCT. No CR was seen, two patients (4%) with SCT had a PR and 19 pts (37%) had SD as their best response. Seven pts were progression-free at 6 months: 2 pts with SCT, 2 with TRS, 1 with liposarcoma, 1 with malignant solitary fibrous tumor and 1 with leiomyosarcoma. Conclusions: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited although some patients had prolonged SD. Activity in pts with SCT warrants further investigation.