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e13009 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability and pharmacokinetics of A in two parallel dose cohort expansion parts, in combination with either G (Part A) or docetaxel (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part A are presented here. Methods: Eligible patients (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once-daily, oral dosing of A in combination with G, given intravenously at Day 1 and at Day 8 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. The primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLTs) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 patients using a 3+3 design. Initial starting dose level was A 30 mg/day and G 1000mg /m², escalating up to A 50 mg/day and G 1250 mg/m², until the MTD was reached, and followed by a PK expansion cohort of 12 patients at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 19 patients have been treated on study with the following baseline characteristics: mean age (53.7 years), women (63.2%) and number of prior chemotherapies (≤2: 26%, >2: 74%). Twelve patients received 2–4 cycles of treatment and five patients received 4 or more cycles. AEs observed in most patients were diarrhea (89.5%) and rash (63.2%). In Cycle 1, DLTs were experienced by one patient out of six receiving A 30 mg and G 1250 mg/m². MTD was exceeded at a dose level of at least A 40 mg/day and G 1250 mg/m². An intermediate dose level of A 40 mg/day and G 1000 mg/m² is currently under evaluation. Conclusions: In patients with relapsed or refractory advanced solid tumors, the combination of A with G is well tolerated, with manageable AEs. Dose finding is ongoing and MTD, safety profile and preliminary evidence of activity are anticipated to be reported at time of presentation.

10042 Background: 40-50% of sarcomas become metastatic. Median survival of metastatic patients has improved over time. The probably multifactorial reasons for such improvement are not fully clear. Noteworthy, for patients with a controlled primary and a limited number of lung metastases, complete resection of their metastases yields survival rates of up to 40% at three years. Advances in surgery, radiotherapy and radiofrequency have fostered the use of local treatments for various metastatic sites (lung, liver, spine...). Methods: A multicentric retrospective study of the Groupe Sarcome Francais (GSF-GETO); approved by the nationally-review board and ethical committee, was conducted to assess the impact of local ablative treatment on overall survival. Patients who had had oligometastases (any site, 1-5 synchronous metastases) at diagnostic or during the course of disease between 2000 and 2010 were included. Results: Median age of the 243 oligometastatic sarcoma patients was 53 years-old (11-86). Patients had grade I, II and III in 7.5%, 29.6% and 63.3% of cases, respectively with various histologies. 69% of patients underwent local ablative treatment of metastases. Median follow-up was 59 months (4-212) for living patients. Median overall survival was 51 months (1-348). On univariate analysis, grade, histology, absence of chemotherapy, local ablative treatment (surgery, irradiation, radiofrequency or chemoembolisation) correlated with survival but not age or site of oligometastasis. On multivariate analyses, grade (hazard ratio HR 0.12 [CI95 0.3-0.6]) and local ablative treatment (HR 3.8 [CI95 2.1-7.1]) remained significant. Conclusions: Local ablative treatment of metastases is associated with better survival in sarcoma patients with oligometastatic disease. The role of the locoregional treatment of metastases and its impact on quality of life should be assessed prospectively.

10056 Background: The management of sarcomas, as for all rare tumors, is hampered by the limited dissemination of medical knowledge. Management within a specialized multidisciplinary sarcoma tumor board (STB) improves compliance to clinical practice guidelines. Since 2010, a national network with a dedicated system for referral, gathering the 26 regional STBs, is supported by the French NCI. Its objectives are to monitor the management of sarcomas and give equal access to expertise and innovative treatments to all patients with sarcoma. We report here the first experience of a web-based data collection from these STBs. Methods: The expected incidence of sarcoma in France is 6.1/105/year, ie 4000 new cases per year. A website collecting all files discussed in the 26 STBs was generated from Jan 2010 ( www.netsarc.org ). The prospective collection of clinical data, STB decision and patient follow-up was implemented in the national database (40 items). Results: 7472 patients were accrued during 2 years, 6202 (83%) had sarcoma, 2860 (46%) were new cases, representing 36% of expected incident cases. The number of new cases discussed in STB increased between 2010 and 2011 (+38%). Patients were referred to the STB (2010-2011; % of cases) prior 1) to biopsy (9%-15%), 2) to first surgery (34%-39%), 3) to adjuvant treatment (35%-34%), after treatment (14%-8%) and at time of relapse (8%-4%). 15% had a metastases at initial diagnosis. The R0+R1 resection rates for primary surgery were 55% vs 42% within vs outside the STB centers of NetSarc. 8% of declared patients were proposed to inclusion into a clinical trial. Conclusions: This web-based tool enabled the description of the activity of the STB at the national level. Clinical practices improved between 2010 and 2011, but 64% of new cases of sarcoma were not discussed in the referent STB prior to surgery. The yearly follow-up of the database will help to monitor evolution of clinical practices.

10062 Background: Trabectedin (T) is a marine-derived alkaloid used to treat advanced soft tissue sarcomas (STS) after ifosfamide and/or anthracyclins failure. Since then, the FSG evaluated the clinical benefit in re-administrating T after an initial hold, either medically indicated or upon patient’s request. Methods: Following an online request, clinical and histopathological data were collected from six centers of the FSG who declared to have rechallenged patients. Baseline data were collected and analyze will be used. Results: From 1999 to 2011, 49 pts with T drug holiday have been identified (26 male/ 23 female), with a median age of 50 y [23-75]. Most frequent histotypes were: myxoid liposarcoma (18, 36.7%), leiomyosarcomas (13, 26.5 %) and well-differentiated/dedifferentiated liposarcoma (9, 18%). WHO grade were 1 in 14 (29%), 2 in 19 (39%) and 3 in 5 (10%) pts respectively. Patients who had a maximum of 2, 3 or 4 therapeutic sequences (TS) with T (drug-holiday and rechallenge) were 41/49 ,7/49 and 1/49 respectively. Median number of cycles for 1, 2, 3 and 4 TS were 7 [3-21], 6 [2-30], 6 [2-9] and 6. Median total number of cycles was 15 [6-43]. Median duration of drug-holiday for 1, 2 and 3 TS were 11 [3-91], 7 [2-29] and 4 months [1-5]. Grade 3-4 toxicities incidence decreased with the number of TS (occurred in 36%, 29%, 14% and 0% of pts with 1, 2, 3 and 4 TS) as well as mean T dose per cycle (1.3 mg/m², 1.2 mg/m², 1.1 mg/m² and 1.1 mg/m² for TS 1, 2, 3, 4). Efficacy decreased with number of TS (Number of CR/PR/SD/PD were 1 (2%)/15 (31%)/33 (67%)/0 for TS1; 0/4 (8%)/29 (59%)/16 (3%) for TS2; 0/1 (14%)/2 (29%)/4 (57%) for TS3 and 0/0/0/1(100%) for TS4). Median overall survival was 5.0 y [2.7-7.3] since T introduction, and 1.5 y [0.1-4.8], 0.8 y [0.5-1.3] and 0.6 y following 2nd, 3rd and 4th T reintroduction respectively. Objective response after TS2 were seen in 4 cases of grade 1 sarcomas. Conclusions: Due to the lack of cumulative toxicities over time with T, its rechallenging in responding patients to T (no progression under T) have to be considered in advanced STS.

3026 Background: Debio 0932 is an oral second-generation heat shock protein 90 (HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier penetration, and promising anti-tumor activity both as monotherapy and combination against a broad range of tumors in pre-clinical models. Here we report the results of the dose escalation part of a phase I study in patients with advanced solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, non-randomized, 3 + 3 dose-escalation study to determine the maximum tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 days of treatment in patients with advanced solid tumours or lymphoma resistant to standard therapy. The starting dose in both treatment groups was 50mg. Doses were increased according to an algorithm based on observed toxicity and dose limiting toxicities (DLT). Tumor assessments were performed every 8 weeks. Results: Patient characteristics and results are summarized below. DLTs occurred at 1600mg in both dose groups. Adverse events (AE) were mostly CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac toxicity was observed. The main reason for treatment withdrawal was progressive disease. Investigator-reported cases of SD and PR were observed. Conclusions: Debio 0932 mono-therapy was generally well tolerated and showed promising signs of efficacy in patients with advanced solid tumors. The recommended phase II dose, established at 1000mg QD, will be tested in an additional 30 patients in an ongoing expansion study. A phase I-II study of Debio 0932 in combination with standard of care in the first- and second-line treatment of NSCLC is planned. [Table: see text]

Background A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability and pharmacokinetics (PK) of A, in two parallel dose cohort expansion parts, in combination with either gemcitabine (Part A) or D (Part B) in pts with relapsed or refractory solid tumours. Preliminary results from Part B are presented here. Methods Eligible pts (advanced solid tumours, Eastern Cooperative Oncology Group Performance Status 0–1) received once daily, oral dosing of A with D, given intravenously on Day 1 of every 3 week cycle. Primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts using a 3 + 3 design. Initial starting dose level was A 30 mg/day and D 60 mg/m2, escalating up to A 50 mg/day and D 75 mg/m2 until the MTD was reached, and followed by a PK expansion cohort of 12 pts at the MTD level. Results To date, 27 pts have been treated in Part B, 18 pts in the escalation phase with A (30–50 mg/day) and D (60–75 mg/m2), and 9 pts in the expansion phase with A 40 mg/day and D 75 mg/m2. Baseline characteristics were mean age (56.4 years), female (44.4%), and number of prior chemotherapies (≤ 2: 48%; >2: 52%). Adverse events (AEs) were manageable and the MTD was not exceeded in the tested dose range up to A 50 mg/day and D 75 mg/m2. AEs were diarrhoea (92.6%) and asthenia (77.8%). Selected dose level for the expansion cohort (A 40 mg/d with D 75 mg/m2) was based on the potential for diarrhoea and rash during later cycles. At this dosage, events qualifying for DLT such as febrile neutropenia (2), diarrhoea Grade 3, hypokalaemia Grade 3, hyponatraemia Grade 3, increase of creatininaemia Grade 2 and oral mucositis, were observed in 7 pts. Conclusions Based on the rate of DLTs observed at 40 mg/day A + 75 mg/m2 D, the decision was made to evaluate further the A 30 mg/day + D 75 mg/m2 dose regimen in an additional cohort of 12 pts. Additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation. Disclosure J. Bennouna: I have received honoraria from roche, boeringher, amgen for advisory board. It is for myself. H. De Mont-Serrat: Employee of Boehringer Ingelheim. P. Squiban: Employee of Boehringer Ingelheim. I. Tschoepe: Employee of Boehringer Ingelheim. All other authors have declared no conflicts of interest.

10020 Background: There is no standard of care for both rare sarcomas. Regarding, the important vascularization of EHE and SFT, we explored the activity/toxicity of So in pts with these sarcomas. Methods: We conducted a multicenter one-step phase II trial of So (800 mg/d). The primary endpoint was the 9-months progression-free rate (9-PFR). According to EORTC criteria, So is considered as promising drug if 6-PFR≥14%. All pts have had documented progressive disease at entry. Results: 20 pts (15 EHE & 5 SFT) were enrolled from June 2009 to February 2011 in the 8 participating institutions. 12 men and 8 women. Median age was 57. The most common primaries were superficial trunk (8 cases) and liver (4 cases). PS were 0 in 10 cases, 1 in 7 cases and 2 in 3 cases. 16 pts had metastasic disease , especially in lung (15), liver (6) and bone (4). Eight pts received prior chemotherapy (Doxorubicin : n= 8 cases and taxane : n =3). The median So treatment duration was 124 days. 9 pts experienced grade-3 toxicities; the most frequent grade-3 toxic events were hand foot syndrome (5 pts), myalgia (1), stomatitis (1), anorexia (1), diarrhea (1) and arterial hypertension (1).Because of this toxicity, treatment discontinuation was necessary in 6 cases and dose reduction was necessary in 5 pts. The 9-PFR was 6/18 (33.3% [11.5-55.1]). The 2, 4 and 6 PFR were 15/18 (83.3%), 8/18 (44.4%) and 7/18 (38.8) respectively We observed 2 partial responses lasting 2 and 9 months in 2 pts with EHE. Analysis of the predictive value of circulating pre-angiogenetic biomarkers is ongoing. Conclusions: According to the STBSG-EORTC criteria (3-PFR≥40% & 6-PFR≥14%), So is a promising drug for EHE and SFT pts. Further trials is needed, especially a discontinuation randomized trial.

2570 Background: Vinflunine (VFL) (Javlor) is a novel microtubule inhibitor indicated in monotherapy for the treatment of advanced or metastatic urothelial transitional cell after platinum failure ...

Background: A novel combination of oral lapatinib (LPT), a selective dual ErbB1/ErbB2 targeted drug, + iv vinorelbine (VNR), a cell-cycle inhibiting agent, could provide a high-potential treatment for locally-advanced or metastatic HER2-overexpressing breast cancer refractory to first or second-line chemotherapy associated to trastuzumab. LPT has been shown to be a strong inhibitor of CYP3A4 which is also mainly involved in VNR metabolism. In this study we investigated the potential pharmacokinetic (PK) interactions related to the association of VNR and LPT. Methods: Women with HER2+ locally advanced or metastatic breast cancer progressing after ≤ 2 lines of trastuzumab-based treatment, were treated with LPT starting 7 days (D) (D-7 to D0) before adding VNR on a D1 & D8 q3w IV schedule. LPT was given orally continuously. Dose levels [DL, LPT (mg)/VNR (mg/m2)] ranged from 750/20 to 1,250/30. A total of 29 patients, 36 to 75 years old, were treated by the association of LPT + VNR. For PK analysis, 7 time point samples were collected on D1 of cycle 1 for LPT and VNR assays. For VNR and LPT respectively, whole blood and plasma concentrations were measured using UPLC coupled with tandem mass spectrometry validated methods. Population PK was modelled using a non linear mixed effect model program (Monolix version 3.1s) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). Results: A three-compartment open model adequately described VNR time versus concentration courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters (clearance : CL, volume of distribution : V, inter-compartmental clearances : Q) except for Q3 and V3. The population PK parameters obtained for the structural model were: CL=40.2 L/h, V1=8.49 L, Q2=46.9 L/h, V2=1290 L, Q3=61.9 L/h and V3=60.9 L. Influence of platelet counts and LPT dose values on blood VNR CL were significant according to the Bayesian Information Criteria (BIC). A one-compartment model adequately fitted the LPT plasma concentration-time data. The population PK parameters were CL=27.9 L/h, V=61.5 L and the absorption constant, ka=0.071 h−1. The ISV were 55.7% and 81.7% for CL and V respectively. No covariate effect, including body surface area and VNR dose values on any PK parameters for LPT could be identified. Conclusions: A PK interaction occured between VNR and LPT. When the LPT dose level increased, the VNR CL decreased significantly, probably due to CYP450-3A4 interaction. The LPT dose which should decrease VNR CL by 50% was defined as 1790 mg. No covariate effects on any LPT PK parameters had been identified. A PK/PD modelling using tumour evaluation and absolute neutrophil count (ANC) is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5468. doi:10.1158/1538-7445.AM2011-5468

Background: BN83495/STX64 is an irreversible steroid sulfatase (STS) inhibitor blocking the hydrolysis of sulfated estrone E1S and dehydroepiandrosterone DHEAS to their unsulfated active forms and thereby preventing conversion to Estradiol (E2) and Androstenediol (adiol), respectively. A phase I dose escalation study was conducted in post-menopausal women (PW) with ER+ metastatic breast cancer (MBC). The aim of the study was to determine the optimal biological dose (OBD) defined as the dose at which STS inhibition in peripheral blood mononuclear cells (PBMCs) ≥ 95% after 7 (D7) and 28 (D28) days of repeated oral daily administration and which also showed a maximal reduction in plasma E2 and adiol levels at D28 with no drug-related Grade 3 (Gr 3) or higher toxicity. Pharmacokinetics (PK), safety, tolerability and anti-tumour activity of BN83495 were also assessed.Methods: Patients (pts) had received at least one line of hormone therapy (HT) and at most 2 lines of chemotherapy (CT) in the adjuvant and/or advanced disease setting. Three to six pts were recruited into each of 5 sequential dose cohorts (1, 5, 20, 40 and 80 mg). The steady-state PK of BN83495 were assessed in all pts. Serum concentrations of E2 and Adiol were determined pre-dose, on D7 and D28 by HPLC-MS/MS analysis. Objective antitumor response was assessed according to RECIST criteria (version 1.0).Results: 29 pts were evaluable for safety. All had received one prior HT for MBC (Aromatase Inhibitors (AI): 86.2% Tamoxifen: 13.8%) and 12 (41.4%) received 2 lines of HT for MBC. BN83495 was well tolerated at doses up to 40 mg. Gr 3 fatigue with positive rechallenge was observed after 3 months of treatment in one pt at 80 mg. The main toxicity was dry skin Gr≤2 (N=12) that was observed in some pts in all cohorts from 20 mg up and was treated with emollient creams. Other toxicities included Gr 1/2 fatigue (N=6), hot flushes (N=3) and nausea (N=2).27 pts were evaluable for efficacy and hormone and STS evaluation. 14 pts received ≥ 3 months treatment. There were 3 SD ≥ 6 months, one each at 13 months (#020, 40 mg), 8 months (#015, 20 mg) and 7 months (#027, 80 mg, hormone resistant pt). Biopsy-proven erythematous skin infiltration in one patient (#027) was no longer visible after 1 month of treatment. Nearly complete STS enzyme inhibition was observed at all doses. The OBD was determined to be 40 mg. At this dose, mean Adiol reduction was -54.0% (-74.0—34.0) and E2 was –27.4% (-47.6- -7.2).An additional cohort (6 pts) was enrolled at 40 mg and FDG PET-scan was performed. Decrease >25% in hypermetabolic volume was noted in 2/5 lesions in 2 patients for whom data are available.Conclusion: BN83495 was well tolerated. Disease stabilizations ≥ 6 months were observed in this heavily pre-treated population including in one hormone resistant pt. The OBD was determined to be 40 mg. Complete FDG-PET scan data will be presented. Based on data obtained so far, BN83495 has shown activity. The study is ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4097.

Background: Lapatinib is effective in overexpressing HER2 LAMBC pts. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Both drugs use the same main metabolic pathway: Cytochrome P450 3A4. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies, and looking for the PK interactions between the 2 drugs.Methods: Women with HER2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7 day (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w iv regimen. L was given po continuously. G-CSF as primary prophylaxis of febrile neutropenia (FN) was not permitted. Dose levels (DL) (L mg/VNR mg/m²) ranged from 750/20 to 1250/30 with 3 patients per DL. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. PK time points analysis was performed on plasma for L and whole blood for VNR. For both drugs the analytical method was Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry (MS-MS) as detection. VNR PK parameters were estimated by nonlinear mixed effect modeling (NONMEM) and L PK parameters were estimated by non compartmental software (MicroPharm).Results: Seventeen pts and 68 PK time points were available for VNR analysis. VNR was ascribed to a tri-compartment model. When considering all VNR data together, VNR clearance (CL) was 37.8±16.7 L/h, while it showed a gradual decrease according to specific dose of L: 47.5±20.4 L/h for L 750 mg (3 patients) vs 35.6±4.3 L/h for pooled data for L 1000 and 1250 (14 patients). This trend was not significant likely due to low number of patients treated at lower dose of L, while no significant difference was observed between L 1000 and L 1250. The mean elimination half life time (t1/2) of VNR was 0.12 h. Six patients and 42 PK time points were analyzed for L. L CL were respectively 83.8 ± 41.3 and 57.1 ± 5.5 L/h for patients who received 750 mg (3 patients) and 1000 mg (3 patients) of L with 20 mg of VNR. The mean elimination half life time (t1/2) of L was 2.89 h.Conclusions: A potential PK interference occurred between VNR and L. When the dose of L increased, both VNR and L CL decreased, likely due to CYP450-3A4 interactions. This trend should be confirmed by the PK analysis of L and VNR in more patients, including an intermediate DL (1250/22.5) still ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5091.

2539 Background: SSR244738 is a new cytotoxic agent (G2-cell cycle inhibitor). In this first in man study the original schedule of administration was an IV infusion once every 3 weeks (Q3W); and due to the high clearance variability, 1300 mg/m2 was considered the maximum administered dose (MAD). The study was amended to test the twice weekly schedule (D1-D4-D8-D11-D15, every 3 weeks). Methods: Standard escalation was used in cohorts of 3–6 pts. PK profiles (up to T48h or T96h) were obtained in each pt after the 1st and the 5th administration (D1 and D15) of Cycle 1. In the Q3W, there was a trend to lower clearance (CL) in CYP2C9 *3/*3 and *1/*3 genotype pts therefore genotype samples were analyzed at baseline to identify poor metabolizers (PM) and adjust-dosing accordingly. Results: 22 heavily pretreated patients received SSR244738 at doses of 200 (3 pts), 280 (4 pts), 400 (3 pts), 560 (3 pts), 780 (3 pt), 1000 (6 pts; one pt was a PM and received 500 mg/m2). 15 females, 7 males, median age: 60 years (29–82), ECOG: (0:12, 1:9, Unk:1). Main tumor types: ovary, lung, breast, colon and prostate. Nb cycles/pts: > 2 cycles/21 (95%), > 4 cycles/9 (41%), > 6 cycles/6 (27%), > 8 cycles/2 (9%). The most common reason for treatment discontinuation was disease progression. DLT was seen in 2 pts at 1000 mg/m2 dose level: one patient had febrile neutropenia associated with Grade 3 mucositis and the second patient had Grade 3 neutropenia, which caused a treatment delay. Both pts showed high SSR244738 plasma exposures on D15. SD was reported in 11 patients. No CRs or PRs were observed. SSR244738 exhibited an overall low plasma CL (mean [range]: 0.9 [0.3–2.1] L/h). CL slightly decreased with repeated administration. The distribution volume was low [Vss mean (CV%): 11.6 L (30%)] and the terminal half life was long [mean (CV%): 15.6 h (58%)]. No deviation from dose proportionality could be observed, despite the moderate-to-high inter-individual variability (CV2/cycle). [Table: see text]

2518 Background: This phase I study of SSR244738, a G2-cell cycle inhibitor cytotoxic agent, was aimed to establish the dose limiting toxicities (DLT), the maximum administered dose (MAD) and to characterize the PK profile of the proposed schedule. Methods: SSR244738 was administered as one-hour IV infusion every 3 weeks in pts (selected according common phase I criteria) starting with a modified accelerated dose escalation scheme. PK profiles (up to day 8) were obtained in each pt after the 1st administration. CYP2C9 and CYP3A5 genotypes were analyzed to identify pts’ metabolizer status. Results: 2 centers enrolled 14 heavily pretreated pts: 5 females, 9 males, median age: 52 years (32–67), ECOG PS: 0 (93% pts); main tumor types: head and neck, lung, melanoma, and breast. 40 cycles (median = 2, range: 1–11) were administered in 6 dose levels (DL) ranging from 165 to 1,300 mg/m2. Accelerated dose escalation was stopped at 660 mg/m2 for non-proportionally increase of PK parameters respect to the dose administered . SSR244738 was well tolerated up to 1,300 mg/m2: one DLT (abnormal liver function tests ALFT) was reported in one breast cancer pt with liver metastases. Only one pt (hepatocarcinoma) was withdrawn from the study due to toxicity (ALFT) after 3 cycles at 1,000 mg/m2. 2 stable diseases were reported. PK data: mean T1/2 of 23h (range: 9.20–127), mean Vss: 11.1 L (6.43–15.8) and mean Clearance (CL): 0.71 L/h (0.041–1.43). This large variability of the CL (CV% =63%) could in part be explained by CYP2C9 genotype: so far CL is 0.6 in extensive metabolizers. Conclusion: Due to the high CL variability, 1300 mg/m2 is considered as the MAD. 3 pts will be accrued at 1,300mg/m2 to complete the DL (a reduced dose will be given to CYP2C9 PM). Weekly and twice-weekly schedules will be tested. No significant financial relationships to disclose.

3133 Background: SR271425, a novel DNA-binding cytotoxic agent has a promising broad spectrum of antitumor activity in preclinical models, independent of the schedule of administration. In addition...

5049 Background: IP epinephrine (EPI) has been shown to enhance the accumulation and antitumor activity of IP cisplatin (CDDP) in rats with peritoneal carcinomatosis (Duvillard et al., Int J Cancer, 1999). EPI activity was related to the vasoconstriction of the peritoneal vascular bed which limits CDDP peritoneal leakage and enhances drug penetration into tumor nodules. A phase I study was conducted to evaluate the local and systemic tolerance of IP EPI in association with IP CDDP. Methods: Between 02/2000 to 06/2003, 17 patients (pts) with refractory peritoneal carcinomatosis (15 ovarian, 1 colorectal, 1 mesothelioma; 1 M/16 F), median age of 64 years (range 52–77), PS 0–1, and normal organ and cardiovascular function were enrolled. CDDP (total dose of 100 or 120 mg), associated with increasing concentrations of EPI, was given intraperitoneally in 2 or 3 liters of saline solution over 3 hours. Plasma and peritoneal concentrations of EPI were determined by HPLC. Results: A total of 52 intraperitoneal cour...

e21533 Sarcomas of the digestive tract (excluding GISTs) (SDT): a study of 63 patients from the French Sarcoma Group (GSF) database Background: The natural history of SDT has been rarely considered...

10546 Background: Elderly GIST patients (pts) represent a consistent portion of all GIST pts, but are under-represented in clinical trials. Data on benefits, tolerance of SU in elderly GIST pts and their specific outcome are very limited. Methods: Charts of elderly pts (≥ 65 yrs)treated with SU in routine clinical practice from 11 Centres of the FSG were reviewed to evaluate the efficacy and safety of SU. Results: 71 elderly GIST pts were reviewed, with a median age of 74, [distributed as 65-74, n=36; 75-84, n=30; ≥ 85, n=5], 41 (57%) men, with median ECOG-PS= 1 (0-2), and median active comorbities of 1 (0-4). SU was administered after progression on first-line Imatinib (400 mg/d for 21 pts, 400 then 800 mg/d for 45 pts) or masitinib (5 pts). SU was started at 50 mg/d 4-wks-on/2 wks-off in 37 pts (52%), at 37.5 mg daily in 32 pts (45%), and at 25 mg daily in 2 pts. All but 2 pts experienced at least one adverse event (AE). Drug related AE were mainly of grade 1 or 2 (298/388, 76%), and medically manageable. Most frequent AE were fatigue (20%), diarrhea (11%), mucositis (7%), abdominal pain (7%), hand-foot syndrome (6%), neutropenia (6%), and hypertension (5%). Permanent dose reduction was reported in 33 pts (46%). In 17 pts (24%) SU was permanently stopped due to grade 3 or 4 AE. ; this occurred within 3 months after starting SU in 10 pts. At a median 36 months follow-up, 53 pts progressed, and 28 pts were alive. The median PFS and OS were 10.2 (0.2-54) and 21 (0.5-77) months, respectively. Univariate analysis showed that age (≤ 80), PS (

11030 Background: Treatment (trt) options for metastatic OST are scarce. Following failure of standard 1st line therapy pts who relapse present a challenging trt dilemma, and have poor prognosis. Surgical removal of all mets is essential. Currently, there are no standardized 2nd line trt options in relapsed OST. Methods: Pts were identified from 2 sarcoma databases; Netsarc and ConticaBase. Clinical data prospectively registered in the databases were supplemented with retrospective review of the medical records. Results: From January 2009 to December 2016, we identified 99 pts, in 12 FSG centers; 30 with synchronous (SC) and 69 with metachronous (MC) mets, with 62 males. Median age was 25 years (18-53). Total number of mets was 1 for 31 pts, 2-5 for 26 and > 5 for 42. Mets sites were lung, bone and other in 77, 14 and 22 pts respectively. Median time to first MC mets was 22 months (mo) (4-97). All pts except 10 with MC mets received a 1st line systemic trt for relapse, 65 a 2d-line, 38 a 3d-line, and 20 a 4th line, with 27 pts included in a clinical trial. Sixty five pts had local trt of distant mets (surgery for 54, irradiation for 5 and radioablation for 6). Eighteen pts had repeated thoracotomies (2 for 13 pts, 3 for 5, 1 for 1 pt). Nine of 10 MC mets pts (with ≤ 5mets) who never received any systemic trt had complete mets resection, 1 had mets radioablation, all were alive at last follow-up (FU). Median FU was 16.5 mo (2-132). Median progression free survival (PFS) and overall survival (OS) were 5.5 (95%CI 4-7) and 16.5 mo (95%CI 10-25) respectively. In multivariate analysis; > 5 mets, time to 1st mets < 24 mo, were negative prognostic factors on OS and PFS (p= 0.03, 0.01 and p=0.013, 0.00 respectively). Bone mets and absence of mets surgery were negative prognostic factors on OS only (with p=0.012, 0.008). Conclusions: Adult OST pts with distant mets are heterogeneous with poor prognosis. Complete surgery of distant mets remains essential. In reference sarcoma center, OST pts at relapse with > 1 mets commonly receive >1st line of systemic trt, and are included in clinical trial. Multidisciplinary trt combining complete mets local trt and systemic therapy seems to be rational.

10504 Background: RE is a multikinase inhibitor that has demonstrated activity in gastrointestinal stromal tumors. We investigated its activity and safety in anthracycline pretreated metastatic sof...

10014 Background: Despite promising phase II trial results, most of new drugs failed to improve the overall survival (OS) in ASTS pts. The choice of the endpoint in early trials remains crucial. We have evaluated the Growth Modulation Index (GMI) as potential endpoint. The GMI is defined as the Time To Progression with the second (or n+1) line of chemotherapy (TTP2) divided by the TTP with the first (or n) line (TTP1). Methods: We have carried out a retrospective multicenter study in pts receiving second-line chemotherapy after failure/intolerance to doxorubicin-based regimens. Data collected included best response(s), TTP1 & TTP2 and OS. Treatments have been classified as "active" treatment according to the EORTC- STBSG criteria (3-month Progression-free rate >40% or 6-month PFR>14%: including trabectedin, ifosfamide, gemcitabine+docetaxel for all subtypes and weekly paclitaxel for angiosarcoma) versus non-active drugs. Comparisons used chi-2 tests and Log-rank tests. We performed a logistic regression analysis for identifying factors associated with longer GMI. Results: The study population consisted in 106 men and 121 women, the median age was 57 years. 110 pts (48.4%) have received "active drugs". The median TTP1, TTP2 and GMI were 197 days, 134 days and 0.75, respectively. The median OS was 446 days. 70 pts experienced GMI>1.33 (30.6%). There was a strong relation between best objective response and GMI (p1.33 were 324, 302 and 710 days, respectively (p1.33 in logistic regression analysis: age, gender, histological subtypes, grade, metastasis locations, interval between diagnosis & metastasis, association with ifosfamide or dacarbazine in 1st-line regimen or treatment with "active drug" in second-line. Conclusions: GMI seems to be an interesting endpoint providing additional information compared to classical criteria. GMI>1.33 is associated with significant improvement of the OS.

10506 Background: Ombrabulin (AVE8062) is a vascular disrupting agent that damages established tumor vasculature and has demonstrated synergistic antitumor activity with cisplatin in vivo. In a phase I study, ombrabulin 25 mg/m² plus cisplatin 75 mg/m² was identified as the recommended dose in pts with solid tumors (AACR 2008; Abs 08-AB-4925). This phase III study evaluated the efficacy and safety of ombrabulin plus cisplatin in pts with advanced soft-tissue sarcoma (NCT00699517). Methods: Pts (aged ≥18 yrs, ECOG PS ≤2) with metastatic soft-tissue sarcoma who had received prior anthracycline and ifosfamide, with ≤2 prior chemotherapies for advanced disease, were randomized (1:1) to receive either ombrabulin 25 mg/m² or Pbo plus cisplatin 75 mg/m² every 3 weeks. The primary objective was to compare progression-free survival (PFS) between arms; secondary objectives included overall survival (OS) and safety. Results: Overall, 355 pts (median age 52 yrs; 51.5% male) were randomized (176 ombrabulin, 179 Pbo) in 44 centers worldwide. Median duration of follow-up was 27.9 and 30.5 months in Pbo and ombrabulin arms, respectively. PFS analysis showed a statistically significant improvement with ombrabulin (median 1.54 vs 1.41 months Pbo; HR=0.76, 95% CI 0.59–0.98; p=0.0302), with 3- and 6-month rates in favor of ombrabulin vs Pbo: 35.4% vs 24.9% and 19.3% vs 10.6%, respectively. A trend for an improvement with ombrabulin was observed in 3 of the 4 prespecified histology strata: liposarcoma, leiomyosarcoma, and “other”, but not for pleomorphic. Analysis of OS did not show statistically significant improvement with ombrabulin (median 11.43 vs 9.33 months Pbo, HR=0.85, 95% CI 0.67–1.09). OS rates at 1 year were in favor of ombrabulin (48.6% vs 42.4% Pbo). Grade 3/4 TEAEs more frequently seen with ombrabulin included neutropenia (19.2% vs 7.9% Pbo) and thrombocytopenia (8.5% vs 3.4% Pbo). Conclusions: Although this trial met its primary efficacy endpoint, the combination of ombrabulin and cisplatin did not demonstrate sufficient clinical benefit in pts with advanced soft-tissue sarcoma to warrant further study. Clinical trial information: NCT00699517.