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Purpose A phase III study comparing eribulin with dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma showed a significant improvement in overall survival (OS) for the eribulin arm, with a manageable toxicity profile. We now report the histology-specific subgroup analysis of the efficacy and safety of eribulin compared with dacarbazine in patients with LPS, an independently randomized stratified subgroup of this phase III trial. Methods Patients ≥ 18 years with advanced or metastatic dedifferentiated, myxoid/round cell, or pleomorphic LPS incurable by surgery or radiotherapy were included. Patients with Eastern Cooperative Oncology Group performance status ≤ 2 and two or more prior systemic treatment regimens, including one with anthracycline, were randomly assigned 1:1 to receive eribulin mesylate (1.4 mg/m2 intravenously on days 1 and 8) or dacarbazine (850, 1,000, or 1,200 mg/m2 intravenously on day 1) every 21 days. OS, progression-free survival (PFS), and safety were analyzed. Results In the LPS subgroup, OS was significantly improved: 15.6 versus 8.4 months (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P < .001) with eribulin versus dacarbazine, respectively. Longer OS with eribulin was observed in all LPS histologic subtypes and in all geographic regions evaluated. PFS was also improved with eribulin versus dacarbazine (2.9 v 1.7 months, respectively; hazard ratio, 0.52; 95% CI, 0.35 to 0.78; P = .0015). Adverse events were similar between arms. Conclusion In patients with previously treated LPS, eribulin was associated with significantly superior OS and PFS compared with dacarbazine. Eribulin represents an important treatment option for patients with LPS, a sarcoma subtype for which limited effective systemic treatments are available. Further studies are justified to explore the role of eribulin in earlier lines of therapy as well as in combination with other agents.

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and PDGFRA kinase signaling. In the INVICTUS study (NCT03353753), patients with advanced GIST (≥4th-line) receiving ripretinib had a median progression-free survival (mPFS) of 6.3 months vs 1.0 month for patients receiving placebo (HR = 0.15, p

11563 Background: ES is a rare, aggressive subtype of STS for which cytotoxic chemotherapy has limited effectiveness. TAZ, an FDA-approved EZH2 inhibitor, has shown single-agent clinical activity and a favorable safety profile in patients with metastatic or locally advanced ES. In preclinical studies, TAZ has shown synergistic antitumor activity with DOX, which is often used as frontline treatment for STS. Here, we present results of the phase 1b study (NCT04204941), designed to assess the recommended phase 3 dose (RP3D), safety, and efficacy of TAZ + DOX in patients with advanced STS. Methods: The open-label, phase 1b portion of this study enrolled adult patients with previously untreated advanced STS. A standard 3 + 3 design was used to assess TAZ 400 mg, 600 mg, and 800 mg orally twice daily in combination with DOX (75 mg/m2 intravenously on day 1 of each cycle, for up to 6 cycles) as frontline therapy. Dose-limiting toxicities (DLTs) were predefined in the protocol. The RP3D of TAZ was determined by Scientific Review Committee review of the safety and pharmacokinetic data from the phase 1b trial, with a target DLT rate of < 33%. Results: As of February 1, 2021, 16 patients are enrolled, including 2 with ES; 10 are still receiving TAZ + DOX and 6 have discontinued (5 due to disease progression, 1 due to patient withdrawal). The median age was 49.5 years (range, 29–82) and all had unresectable STS. Median (range) time on treatment was 13 (0.1–51.1+) weeks across all dose levels evaluated. Two DLTs, both of febrile neutropenia, were observed, one in the TAZ 600 mg + DOX cohort (n = 1/6, 17%), and one in the TAZ 800 mg + DOX cohort (n = 1/3, 33%). When used in combination with DOX, the RP3D of TAZ was 800 mg. Grade 3 or 4 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 13/16 (81.3%) patients. The most common (≥ 20%) TR-TEAEs were neutropenia (n = 11, 69%), anemia (n = 10, 63%), fatigue (n = 10, 63%), stomatitis (n = 9, 56%), nausea (n = 8, 50%), febrile neutropenia (n = 7, 44%), constipation (n = 6, 38%), vomiting (n = 6, 38%), and decreased appetite (n = 5, 31%). TR-TEAEs were defined as attributable to either study agent. Conclusions: The combination of TAZ + DOX was generally well tolerated in this dose finding study in patients with advanced STS. The RP3D to be tested in the phase 3 randomized, double blind, placebo controlled study is TAZ 800 mg twice daily + DOX. The safety profile of this combination is consistent with the respective safety information for TAZ and for DOX. The TR-TEAEs include known toxicities of DOX or TAZ. Further comparison with DOX + placebo in the phase 3 trial will aid in assessing efficacy and safety of the combination of TAZ + DOX. The global phase 3 confirmatory trial will enroll patients with ES who have unresectable disease and have had no prior systemic therapy. Clinical trial information: NCT04204941.

11517 Background: Doxorubicin (doxo) remains standard first-line therapy for advanced STS. Doxo in combination with olaratumab (O) demonstrated superior clinical activity compared to doxo alone in a Ph 2 trial (NCT01185964), although this was not confirmed in the subsequent Ph 3 trial (NCT02451943). Gemcitabine (G) plus docetaxel (D) is a second line therapy for advanced STS. Here, we report a concurrent Ph 2 study that explored a second-line addition of O to G and D for advanced STS (ANNOUNCE 2 NCT02659020). Methods: Adult patients (pts) with unresectable locally advanced or metastatic STS, ≤ 2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. Pts were enrolled from 2 cohorts: O-naïve and O-pretreated. In both cohorts, pts were randomized 1:1 to either O, G plus D or placebo (PBO), G plus D. Pts received 21-day cycles of O (20 mg/ kg cycle 1 and 15 mg/kg other cycles, day (d) 1 and d8), G (900 mg/m2, d1 and d8) and D (75 mg/m2, d8). Pts continued treatment until progression, toxicity, or withdrawal. Randomization was stratified by histology (leiomyosarcoma [LMS] vs non-LMS), prior systemic therapy, ECOG PS, and prior pelvic radiation. The primary objective was overall survival (OS) in the O-naïve population using an alpha level of 0.20. Secondary endpoints included OS (O-pretreated) and other efficacy parameters, as well as safety and pharmacokinetics (PK). Results: 167 pts were enrolled in the O-naïve cohort and 89 pts in the O-pretreated cohort. Baseline patient characteristics were well balanced. OS for O-naïve pts was 16.8 vs 18.0 months (m) (hazard ratio [HR] = 0.95, 95% CI: 0.64-1.40; p = 0.78) for the investigational vs control arm, respectively. Other efficacy outcomes are presented in the table. Safety was manageable across treatment arms. PK parameter estimates for O were consistent with previous studies. Conclusions: There was no statistically significant difference in OS between the two arms in the O-naïve population. However, while not statistically significant, the combination of O, G and D demonstrated favorable OS in the O-pretreated cohort, and PFS and objective response rate (ORR) in both cohorts. For O-naïve pts, a clinically meaningful progression-free survival (PFS) improvement was observed. Further investigations in specific histological subtypes are ongoing. Clinical trial information: NCT02659020. [Table: see text]

e23564 Background: Activity of temozolomide (TEM) and irinotecan (IRI) in recurrent Ewing sarcoma (EWS) was demonstrated. Few data are available on TEMIRI use upfront. Biological predictive factors are lacking. Methods: This multi-institutional retrospective study (NCT03542097) included 59 patients with EWS. 8 patients with very high risk (HR) EWS (multivisceral ± bone marrow) received TEMIRI (TEM 100 mg/m2/day oral, and IRI 40 mg/m2/day intravenous, days 1-5, every 21 days) upfront, 51 patients after relapse (28% in 1st line, 72% ≥ 2nd line). Overall response rate (ORR: CR+PR), SD, and PD, progression-free (PFS) and overall survival (OS) were assessed. The relationship between pre-treatment expression of MGMT and ABCG2 (when FFPE tissue available) with ORR, PFS and OS was evaluated. Results: Median age was 27 years (range 4-62 years): 47 patients (80%) were adults (≥18 years), 35 (61%) had ECOG 0 and 42 (71%) presented with multivisceral disease (+ bone marrow in 5). MGMT was positive in 16/30 (53%), ABCG2 in 4/33 (12%). ORR for upfront TEMIRI (n = 8) was 50% (CR + PR = 1 + 3), with SD 50%, while in recurrent EWS (n = 49, 2 patients no measurable by RECIST) ORR was 31% (CR + PR = 4 + 11), SD 38%, and PD 31%. A better ORR was observed in adult (p = 0.008) & ECOG 0 (p = 0.001) patients; MGMT & ABCG2 expression did not influence ORR. 6-mos PFS was 87% after TEMIRI upfront, 43% at recurrence (p = 0.06), and 65% vs 28% (p = 0.02) for ECOG 0 vs ECOG 1-2, respectively. 6-mos PFS was 62% in MGMT+ vs 33% in MGMT- (p = 0.4) and 75% in ABCG2+ vs 50% in ABCG2- (p = 0.7). Median time to progression (TTP) with upfront TEMIRI was 9 months (range 5-28 months), with 1 patient with ongoing CR at 56 months; median TTP at relapse was 3 months (1-29 months). MGMT and ABCG2 expression did not influence 1-yr OS, whereas ECOG (0 vs 1-2) did (88% vs 31% p < 0.001). Grade 3-4 diarrhea, neutropenia, and thrombocytopenia incidence was < 5%, 1 patient with recurrent kidney EWS died of acute liver failure. Conclusions: TEMIRI showed promising activity in a very unfavorable cohort of EWS patients, with manageable toxicity. Performance status correlated with 6-month PFS & OS whereas MGMT & ABCG2 did not. Clinical trial information: NCT03542097 .

11564 Background: Epithelioid sarcoma (ES) is a rare, aggressive soft tissue sarcoma characterized by loss of inhibitor of integrase 1 (INI1), allowing enhancer of zeste homologue 2 (EZH2) to repress cell differentiation and promote tumorigenesis. Tazemetostat (TAZ) is a selective inhibitor of EZH2 approved by the FDA for treatment of patients (pts) aged ≥16 years with metastatic or locally advanced ES ineligible for complete resection. Methods: This open-label, multicenter, multi-cohort phase 2 study (NCT02601950) evaluated safety and efficacy of TAZ in pts with INI1-negative tumors. ES pts were enrolled in Cohorts 5 and 6; pts in Cohort 6 underwent mandatory pre-dose (at screening) and post-dose biopsies (at Day 1 of cycle 2). Herein, we report the interim efficacy and safety data from Cohort 6. Results: As of July 31 2019, 44 pts were enrolled into Cohort 6 and treated with TAZ 800 mg BID. The objective response rate (ORR) was 11.4%; 4 pts (9.1%) had a partial response and 1 pt (2.3%) had a complete response (Table). Another 17 pts (38.6%) had stable disease (SD). 18 pts had progressive disease; 13 of these pts remained on study beyond progression. Progression-free survival (PFS) and overall survival (OS) at 56 weeks were 19.4% and 59.4%, respectively. In a pooled posthoc analysis of 106 ES pts from Cohorts 5 (n = 62), and 6, ORR was 13.2%. Grade 3–4 adverse events (AEs) were reported in 16 pts (36.4%), most commonly anemia (6.8%; n = 3) and tumor pain (6.8%; n = 3). 3 pts (6.8%) experienced grade 3–4 treatment-related AEs. One pt discontinued study drug and there were no treatment-emergent dose reductions or treatment-related deaths. These safety data from Cohort 6 are consistent with previously reported data from Cohort 5. 19 paired biopsies were included for translational endpoint analyses. Preliminary RNA seq and pathway analyses are currently ongoing and updated data, including additional biomarker data will be presented. Conclusions: Consistent with previously reported data from the completed Cohort 5, TAZ demonstrated clinically meaningful, durable, single agent activity in ES pts. Efficacy data from Cohort 6 continue to mature with 8 patients still on treatment. TAZ was well tolerated with a low incidence of treatment related AEs. Clinical trial information: NCT02601950 . [Table: see text]

e16643 Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in a variety of solid tumors resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, Phase 1, open-label, single-arm study of olutasidenib in non-CNS solid tumors. Methods: Patients with advanced relapsed/refractory (R/R) mIDH1 solid tumors received olutasidenib 150 mg BID, orally. Following a dose confirmation cohort (Phase 1b), patients with intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma (CS), or unspecified mIDH1 solid tumors (Other) were enrolled in a Phase 2 efficacy evaluation (NCT: 03684811). Results: As of 31-Oct-2019, 44 patients with relapsed or refractory mIDH1 solid tumors were treated with olutasidenib. Diagnosis included: IHCC (n = 26), CS (n = 13), and Other (n = 5). The median age was 58 years (range: 29-81) and 43% were male. Median number of prior treatments was 2 (1-10). mIDH1 status was locally determined (IHC, NGS or PCR): R132C (61%), R132G (7%), R132S (7%), R132H (2%), R132L (2%), Others (2%) & unspecified (18%). Fourteen patients discontinued treatment (disease progression [n = 6; 3 IHCC, 2 CS, 1 Other], AE [n = 4; 3 IHCC, 1 CS], PI decision [n = 3; IHCC] & withdraw consent [n = 1; IHCC]). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in > 15% of pts were: nausea (43%), fatigue (25%), decreased appetite (22%), AST increase (18%), ALT increase (16%), and constipation (16%). No protocol-defined DLTs occurred. Best responses by tumor type are shown in the table. Conclusions: Single agent olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in patients with R/R mIDH1 solid tumors. Updated safety and clinical activity, as well as exploratory evaluations of PK/PD will be provided. Clinical trial information: 03684811 . [Table: see text]

11535 Background: Ripretinib is a novel switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits KIT and PDGFRA kinase signaling through a dual mechanism of action. In INVICTUS (NCT03353753), a randomized, double-blind, placebo-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs placebo and had a favorable overall safety profile in patients previously treated with ≥3 prior TKIs. Methods: As part of the INVICTUS trial, patient reported outcome (PRO) measures were collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). In prespecified and additional analyses, ANCOVA models were built to compare changes from baseline to cycle 2 day 1 (C2D1) for PRO measures within the ripretinib and placebo arms and determine the difference between treatment arms. PRO measures included the EQ5D visual analogue scale (VAS) and the C30 physical functioning (PF) and role functioning (RF) scales (all scores range from 0–100; higher scores are better). The C30 overall health and overall QoL questions were also assessed (scores range from 1–7; higher scores are better). Fixed effects included treatment arm, number of previous anticancer treatments (3 vs ≥4), and ECOG score at baseline (0 vs 1/2). Results: Overall, 129 patients were randomized and 128 received treatment (85 to ripretinib 150 mg QD; 43 to placebo). All PRO p-values are nominal, and no statistical significance is being claimed. VAS scores improved an average 3.7 points from baseline to C2D1 with ripretinib vs an average decline of 8.9 with placebo (P = 0.004; improvement or no change, 67% vs 41% of patients, respectively). Similarly, the average PF score improved 1.6 points with ripretinib and decreased 8.9 with placebo (P = 0.004; improvement or no change, 68% vs 44%). RF scores also improved an average of 3.5 points with ripretinib vs a decrease of 17.1 with placebo (P = 0.001; improvement or no change, 77% vs 50%). For the overall health and overall QoL questions, scores increased with ripretinib an average of 0.20 and 0.28, respectively, and decreased 0.78 and 0.76 with placebo (both P = 0.001; improvement or no change, 74% vs 47% and 79% vs 59%, respectively). Conclusions: Based on the 5 PRO measures assessed, when compared with placebo and best supportive care, ripretinib provided patient-benefit in advanced GIST with PRO measures of role and physical function, VAS, overall health, and overall QoL remaining stable. Clinical trial information: NCT03353753 .

826 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Overall population safety (30-600 mg starting doses) and efficacy in the response-evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 [56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with mDOR of 10.2 months (95% CI: 7.2–NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3–NE). Most AEs were grade 1–2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3–4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows impressive activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.

LBA3 Background: Dox is standard therapy in STS. In a Ph 2 trial, olaratumab (a human IgG1 antibody targeting PDGFRα) + dox improved overall survival (OS) and progression-free survival (PFS) vs dox. ANNOUNCE aimed to confirm the OS benefit in advanced STS. Methods: Adult pts with unresectable locally advanced or metastatic STS, anthracycline-naïve, and ECOG PS 0-1 were eligible. Pts were randomized 1:1 to olaratumab (20mg/kg Cycle 1, 15mg/kg subsequent cycles) or PBO on Days 1 and 8 of each 21-day cycle combined with dox (75mg/m2) on Day 1 for up to 8 cycles. After 8 cycles, pts with disease control continued olaratumab or PBO until progression or toxicity. Randomization was stratified by histology, prior systemic therapy, ECOG PS, and geographic region. Dexrazoxane use was allowed to mitigate dox-related cardiotoxicity. Primary endpoints were OS in the intent-to-treat (ITT) population and/or leiomyosarcoma (LMS) subset of the ITT population; the study was designed to be positive if either primary endpoint was met. Secondary endpoints included PFS, response/disease control rates, safety, and pharmacokinetics. Results: 509 pts were randomized: 258 in the investigational and 251 in the control arm. Baseline pt characteristics were well balanced. Dexrazoxane was received by 63.0% vs 65.1% of pts (investigational vs control arm, respectively, for all data). In the ITT population, median OS was 20.4 vs 19.8 months (m) (HR=1.05, 95% CI: 0.84-1.30; p = 0.69) and was 21.6 vs 21.9 m in LMS pts (HR=0.95, 95% CI: 0.69-1.31; p = 0.76). Median PFS was lower in the investigational arm in the ITT population (5.4 vs 6.8 m; HR=1.23, 95% CI: 1.01-1.50; p = 0.04) and in LMS pts (4.3 vs 6.9 m, HR=1.22, 95% CI: 0.92-1.63; p = 0.17). Median dox exposure was 6 vs 7 cycles. Safety was similar between arms. Olaratumab serum concentrations reached levels expected from prior trials. Additional subgroup/biomarker results will be presented. Conclusions: ANNOUNCE did not confirm that olaratumab + dox, followed by olaratumab monotherapy, improves OS over dox in pts with advanced STS. Further analyses are warranted to explore the inconsistent outcomes between the Ph 3 and Ph 2 studies. Clinical trial information: NCT02451943.

11003 Background: ES is a rare soft tissue sarcoma that metastasizes in approximately 30% to 50% of cases. More than 90% of ES tumors lack expression of INI1, an important component of epigenetic regulation. Loss of INI1 function allows another epigenetic modifier, EZH2, to become an oncogenic driver in tumor cells. Tazemetostat, a first-in-class, selective, oral inhibitor of EZH2, has demonstrated tumor regression and favorable safety in phase 1/2 trials. Methods: Data from a phase 2 open-label, multicenter trial of pts with locally advanced or metastatic ES are reported. Efficacy was assessed with primary and secondary endpoints including objective response rate (ORR) by RECIST 1.1, disease control rate (DCR; objective confirmed response of any duration or stable disease [SD] lasting ≥32 weeks), duration of response (DOR), progression-free survival (PFS), overall survival (OS); safety and tolerability were also evaluated. Results: As of September 17, 2018, 62 INI1-negative ES pts were enrolled and treated with tazemetostat 800 mg BID. The median number of prior lines of therapy was 1 (range: 0-9). There were 9/62 (15%) confirmed partial responses (PRs) with an ORR of 15% and DCR of 26%. The DOR ranged from 7.1+ weeks to 103.0+ weeks (median: not reached) with a median OS of 82.4 weeks (95% CI: 47.4, not estimable) for all 62 pts. Tazemetostat was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild to moderate with the most commonly reported adverse events (AEs; ≥10% incidence) regardless of attribution being fatigue (24/62; 39%), nausea (22/62; 35%), and cancer pain (20/62; 32%). Any treatment-related TEAEs of grade ≥3 were reported in 10/62 (16%) pts. TEAEs grade ≥3 reported in ≥2 pts included anemia (6%) and decreased weight (3%). There were no drug-related deaths and a low discontinuation rate (1.7%). Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat achieved disease control in 26% of pts with advanced ES who entered this study. Durable clinical response of the drug was documented. Tazemetostat demonstrated favorable safety with few pts with treatment-related AEs grade ≥3. Clinical trial information: NCT02601950.

11061 Background: TRB is FDA approved drug for the treatment of liposarcoma (Lipo) and leiomyosarcoma (LMS). The aim of this study was to evaluate potential biomarkers associated with prolonged benefit in patients treated with TRB at our center prior to 2016. Methods: We performed a retrospective search of UW/FHCRC CASIS database to identify patients treated with TRB prior to 2016. Demographic variables and clinical variables (such as histology and treatment) were retrieved. Statistics were performed with R 3.4.1 software. Pairwise Pearson’s correlation was calculated for the # of prior chemotherapy regimens with # of TRB cycles. The Kaplan-Meir method was used to evaluate overall survival (OS). Log-rank test was conducted to compare groups in terms of OS. Results: 145 sarcoma patients treated with TRB were identified with a mean follow up of 5 years (generally on NCT01427582 or NCT01343277). Patients averaged 1.9 prior chemotherapy regimens prior to TRB (range 0-7 regimens) and received an average of 5.6 TRB doses (range 1-25 doses). Subtypes are listed on table. The # of prior regimens was negatively correlated with the # of TRB cycles that patients received (pairwise correlation coefficient = -1.77; p=0.034), suggesting that multiple prior treatment lines either made TRB less tolerable or made sarcoma less sensitive to TRB. The median OS for this heavily treated metastatic population was 0.5 years. However, patients who were able to stay on TRB for more than 5 cycles had a significantly higher OS (p=0.001). While only 23% of patients who received less than 5 cycles of TRB were alive at 5 years (95% CI: 0.15, 0.32), 53% of those who received 5 or more cycles of (95% CI: 0.39, 0.65) were alive at 5 years. Conclusions: TRB may be more effective when administered as an earlier line of therapy. Patients who are able to stay on TRB for a longer duration had a significant improvement in OS. Detailed subset analysis will be presented as will initial findings of our biomarker work. These retrospective data warrant further evaluation. Clinical trial information: NCT01427582 or NCT01343277. [Table: see text]

11009 Background: Patients with advanced soft tissue sarcomas (STS) treated with single agent Dox have a median progression-free survival (PFS) of 4.6 months (mo) and response rate (RR) of 14%. Dox sensitizes tumors to Pem through calreticulin release and killing of immunosuppressive cells. Thus we hypothesize that combining Dox + Pem will improve patient outcomes. Methods: A phase I/II trial (NCT02888665) evaluating Dox+Pem was designed for Dox naïve STS and select bone sarcomas with a 1° endpoints of safety (CTCAE v4.03) and response rate (RR) by RECIST 1.1. Patients received one “priming” dose of Pem (200mg IV) prior to starting Dox+Pem Q3wks. Dox+Pem was continued for up to 6 cycles, followed by Pem monotherapy for up to 2 years or progression. The phase I portion used a 3+3 design with 2 Dox doses (45 & 75 mg/m2), followed by a Simon 2-stage expansion. A retrospective study of patients treated at our center on non-ifosfamide containing Dox trials (DoxT) was performed in order to compare our observed PFS with a comparable historic population. Results: Treatment was well tolerated; detailed safety data will be presented. No additional cardiac risk was observed. No DLTs were observed during phase I and 75mg/m2 was selected as the phase 2 Dox dose. The study met criteria for expansion to the 2nd stage. Though the planned enrollment was 41, the study closed after 37 as it was clear that the RR (22% , including phase I patients) would not meet the phase 2 RR target of 29%. However, 59% of patients had stable disease (disease control rate = 81%) with tumor regression in a majority of patients. The median PFS on Dox + Pem was 8.1 mo (95% CI: 6.3, 10.8). Patients treated with Dox + Pem had a significantly longer median PFS compared to the DoxT cohort (4.1 mo, 95%CI 3.0 – 6.6, p < 0.001). Conclusions: Dox+Pem is well-tolerated. While this study failed to meet its 1° RR endpoint, a highly significant improvement in PFS was observed compared with historical controls. This is consistent with findings in other cancers, such as head & neck, where improved clinical outcomes were observed without significant increase in RR by RECIST. A randomized trial of Dox +/- Pem should be carefully considered in light of recent negative trials in STS. Clinical trial information: NCT02888665.

11016 Background: Sarcoma cells are most immunogenic earlier in the disease course and prior to treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Methods: This is an IRB-approved dose-seeking Phase 1/2 protocol using defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks) and escalating doses of T (1.0, 1.2, 1.5 mg/m2 i.v. q 3 weeks), employing the “Cohort of Three” design, followed by a Phase 2 using the MTD of trabectedin. Results: Nine subjects were treated in Phase 1 of the study, and 31 subjects in Phase 2. Safety analysis: at Dose 1: Grade 3 treatment-related adverse events (TRAEs) included fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs included thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs included anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). Efficacy analysis (evaluable patients): At Dose 1: Disease Control Rate (DCR = CR, PR, SD) was 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1), DCR 60%, median PFS, 24 weeks; median OS, > 46 weeks. At Phase 2, MTD Dose 2 (PUPs): Safety analysis (n = 31): Grade 3 TRAEs included fatigue (n = 2), increased ALT (n = 6), increased AST (n = 4), hypernatremia (n = 1), hyponatremia (n = 1), dehydration (n = 1), rash (n = 1), port cellulitis (n = 1), psoriasis exacerbation (n = 1), increased TSH (n = 1), decreased hemoglobin (n = 2), neutropenia (n = 1). Efficacy analysis (N = 23 evaluable): PR (n-5; 2 UPS, 1 synovial sarcoma, 1 liposarcoma, 1 leiomyosarcoma,), BORR 22%, DCR 96%. Median PFS and OS not yet reached. After 4 treatment cycles, one resected tumor showed 80% necrosis and a greater number (30%) of CD8+ killer T cells, in the TME compared to archived pre-treatment tumor. Conclusions: These data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. Phase 2 of the study is on-going. Clinical trial information: NCT03138161.

11022 Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Updated results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥ 1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Safety from the overall population (30-600 mg doses) and efficacy in the response evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 (56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with median duration of response (mDOR) of 10.2 months (95% CI: 7.2-NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3-NE). Most AE were grade 1-2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3-4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows unprecedented activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.

e23570Background: Endoglin (CD105) is an essential angiogenic receptor expressed on Angiosarcoma (AS) tumor cells and vessels that is upregulated following hypoxia and promotes resistance to VEGF i...

e23519Background: Paediatric, adolescent, wild type and syndromic Gastro Intestinal Stromal Tumours (PAWS-GIST) consortium was formed in UK as a joint effort between GIST specialists, patients and ...

11559Background: Treatment options for patients with metastatic sarcoma are limited. Gemcitabine-based schedules have shown activity and in selected patients, re-challenge with a previously success...

71 Background: Soft tissue sarcomas (STS) are heterogeneous tumors which are morbid and lethal. G100 is under investigation in multiple clinical trials and contains a potent TLR4 agonist (oil-in-water emulsion of glucopyranosyl lipid A) that has been tested as vaccine adjuvant. We hypothesized IT G100 would induce robust local and potentially systemic anti-tumor immune response, leading to improved outcomes. Methods: 15 metastatic STS patients with superficial lesions were treated with weekly IT G100 for 8-12 wks; 12 patients received radiation (RT) for 2 wks to start, while 3 received IT G100 for 6 wks prior to RT. Biopsies and PBMC were collected pre and post treatment, and flow cytometry was performed on biopsies. TIL and PBMC were analyzed with TCR deep sequencing. PBMC were analyzed by single cell multiplex cytokine profiling. Results: No grade ≥ 3 toxicity was observed, and local tumor control was achieved in all evaluable tumors (14/14). Treated tumors tracked post-trial (mean 156 days) had persistent local control with 1 CR (7%), 1 PR (7%), and 11 SD (79%). In 3 patients with long term follow up, treated lesions remained controlled vs index lesions (-53% vs +31% at mean 235 days, p = 0.002). In all tumors after G100 alone, T cell infiltration increased. In P14, CD3 live cells in tumor rose from < 1% to 62%. PBMC clonality increased in 8/14 tested including P06, who had 4× increase in clonality and CR in the injected lesion; PBMC and TIL TCR overlap increased from 13.4% to 21.5%. P13 had a 2.3× rise in TIL clonality; the top clone (a CD4 T cell) expanded from 0.1% to 38% and expressed more TNFα than the rest (p < 0.0001). Single cell cytokine analysis of PBMC showed 7/13 (54%) increased in polyfunctionality (producing > 2 cytokines) in CD4 T cells; no consistent increase was seen in CD8 T cells. TNFα levels in pre-treatment monocytes correlated with PFS (R2= 0.5, p = 0.02). Conclusions: IT G100 is a viable agent for local control of metastatic STS lesions. With or without RT, G100 appears to cause CD4 T cell mediated local and systemic response. Combination of G100 with other immunomodulators could induce clinically significant systemic responses, as seen in follicular NHL treated with G100. Clinical trial information: NCT02180698.

11030 Background: TMZ+IRI has significant activity in metastatic ES. Epigenetic silencing of the MGMT DNA gene by promoter methylation has been associated with response to TMZ in glioblastoma. Our aim was to assess if MGMT methylation 1) has a role in ES progression and 2) is predictive of response to TMZ. Methods: 1) In 10 ES cell lines presence of MGMT gene (Real-time PCR), methylation of its promoter (methylation-specific PCR) and protein expression (western blot) were assessed. MGMT protein (IHC) and methylation of its promoter was searched in 97 ES pts samples (74 localized; 23 metastatic). 2) In metastatic ES pts treated with TMZ+IRI, with pre-treatment FFPE tissue and measurable disease, the relation between RECIST response, PFS and MGMT expression (IHC) was assessed. Results: 1) The expression of MGMT gene and its protein was detected and concordant (p = 0.02) in all ES cell lines evaluated; methylation was a rare event. In ES tissue samples the methylation of the MGMT gene was found at a low intensity as compared with the unmethylated gene, but the protein expression was relatively low: 36% in localized, 65% in metastatic pts (p 0.03). 2) 24 pts (median age 19 years, range 3-50 years; F/M: 7/17) treated with TMZ + IRI from 2010 to 2015 were identified. Line of treatment: 8 patients were in 1st line; 16 ≥ 2nd line. Median n of cycles was 6 (range: 2-31). Pattern of metastases: 16 multiple sites, 4 lungs, 3 multiple sites + bone marrow, 1 bone. MGMT was positive in 63% of cases. ORR: 16.5% (1 CR , 3 PR); SD: 50% (13 pts); PD: 33.5% (7 pts). According to MGMT expression the ORR was 11% in negative and 20% in MGMT positive patients (p = 0.8). 6-mos PFS rate was 59% (38-80 %IC), no differece according to MGMT expression (pos 61% vs neg 56%, p 0.7). Conclusions: Whereas in cell lines the MGMT gene and its protein expression is a generalized event, in tissue samples MGMT protein is present in a minority of localized pts, and might be associate with tumor progression. Methylation of MGMT gene does not seem responsible for its regulation in ES, and post-transcriptional mechanisms are more likely to be involved. The presence of MGMT protein does not predict the response to TMZ + IRI in this small series.

TPS11081 Background: AAS is an aggressive soft tissue sarcoma (STS) of endothelial cell origin with an expected median overall survival of 8-12 months. Pazopanib (P) is approved for treatment of advanced STS following progression on chemotherapy. In a retrospective study of 40 AAS patients treated with single agent P the median PFS was 3.1 months and median OS 9.9 months with no complete responses. Endoglin is an essential angiogenic receptor expressed on AAS that is upregulated following VEGF inhibition, and TRC105, an endoglin antibody, given with P produced durable complete responses in AAS patients with median PFS of 5.6 months in refractory patients including those receiving prior P. The TAPPAS trial is the first randomized Phase 3 trial performed in AAS, and was initiated following protocol assistance from the EMA and Special Protocol Assessment from the FDA. Methods: TAPPAS is a randomized multicenter study of TRC105/P vs P alone in the United States and Europe that is actively enrolling cutaneous and non-cutaneous AAS patients and incorporates an adaptive enrichment design. Key inclusion criteria: 0, 1 or 2 prior lines of therapy, ECOG ≤ 1. Primary endpoint is PFS and secondary endpoints include ORR and OS. The initial sample size of 124 patients, followed until 95 PFS events, provides more than 80% power to detect a hazard ratio of 0.55. At the time of interim analysis, projected to occur upon the occurrence of 40 events in approximately 70 patients, the result will be classified as belonging to either the favorable, promising, enrichment or unfavorable zones, based on conditional power. The sample size and PFS events will be unchanged in the favorable and unfavorable zones, and will be increased to a total of 200 patients followed for 170 PFS events in the promising zone. The trial will enroll 100 additional patients, with cutaneous disease only, in the enrichment zone and will follow them until 110 events are observed in the total cutaneous population. An independent DMC will follow the trial for safety and futility. The adaptive design requires the enrollment of fewer patients, preserves type-1 error, and protects power to detect a clinically meaningful survival benefit. (NCT 02979899). Clinical trial information: NCT02979899.

5071 Background: An urgent need exists for new therapies after progression (PD) onAA and enzalutamide (ENZ). Increased PR expression or progesterone-activating AR mutations have been associated with resistance to AR targeting. We aimed to test ONA, a type I PR antagonist with clinical activity in PRpos cancers, in AA/enz-resistant CRPC. In a prospectively defined exploratory analysis, we aimed to report outcome by plasma AR status ( pAR). Methods: This was a multi-institution, open label phase I/II clinical trial in pts progressing after ENZ/AA. Pts were first treated with single agent (SA) ONA using a randomised dose escalation design. ONA at 2 doses was then combined with AA (1000mg od with pred 5mg bid) in pts progressing on AA. The primary end-points were safety, pharmacokinetics (PK) and anti-tumor activity split by p AR. Archival and metastatic biopsies were collected when possible and tested for PR status. p AR was studied using previous methods (Romanel STM 2015). Results: 21 pts received SA ONA (5 = 10mg/ 5 = 20mg/ 4 = 30mg/ 4 = 40mg /3 = 50mg BID) and 15 pts received ONA-AA combination (5 = 30mg ONA BID, 10 = 50mg ONA BID). There were not DLTs or significant LFT abnormalities and no G3/4 adverse events (AE), no treatment discontinuations due to AEs and no SAEs considered related to ONA. PK in SA ONA observed active plasma concentrations and no interaction with AA. Of 32 evaluated pts 15 had a 2105T > A (p.L702H) or 2632A > G (p.T878A) AR mutation detected in plasma pre-treatment and 1 had AR copy number gain. PSA declines were not observed with SA ONA but in 2 pts with combination (-30%, -7%) who were AR normal. The rPFS on SA ONA was 2.8 months for AR normal and 2.6 for AR aberrant (Hazard ratio (HR) 1.41; 95% CI, 0.62-3.72; P 0.48) and on combination was 4.4 months for AR normal (8/15) and 2.2 for AR aberrant (7/15) (HR 6.08; 95%CI, 6.32-221.9; P < 0.001). Conclusions: ONA is safe in CRPC as SA and in combination with AA. There was no difference in rPFS by p AR status for SA ONA but on the combination with AA, pts who were plasma AR normal had a significantly longer rPFS. Clinical trial information: NCT02049190.

11011 Background: Oncogenic mutations in KIT or PDGFRα drive > 85% of GIST. However, primary and acquired mutations in the activation loop of PDGFRα and KIT are not effectively treated by approved therapies. A phase 1 study (NCT02508532) was initiated in advanced GIST to assess the safety, PK and clinical activity of BLU-285, a potent, highly-selective oral inhibitor that targets KIT Exon 17 and PDGFRα D842 activation loop mutants. Methods: Adult patients (pts) with unresectable GIST, who had received ≥2 kinase inhibitors including imatinib or who had a primary PDGFRα D842 mutation regardless of prior therapy, were given BLU-285 once daily on a 4-week cycle following a 3+3 escalation design, which allowed additional accrual to dose levels demonstrated to be safe. Adverse events (AEs) per CTCAE v4.03, PK and plasma/tumor mutant DNA levels were assessed. Response was determined by RECIST 1.1 every 8 weeks. Results: At a 01JAN17 cutoff, 40 pts (21 PDGFRa/19 KIT) have been treated with BLU-285 at doses of 30-600 mg. Median number of prior kinase inhibitor regimens was 4.5 (2-12) KIT/2.5 (0-4) PDGFRα. RECIST 1.1 responses were seen across all dose levels for PDGFRα GIST and at higher dose levels for KIT GIST. Of 17 PDGFRα D842V pts with ≥1 radiographic assessment, 7 had confirmed PR (ORR 41%) and 10 had SD. Of 11 evaluable KIT pts treated at doses ≥ 135 mg, 2 had PR (1 confirmed; ORR 18%) and 5 SD. BLU-285 is rapidly absorbed (Tmax 2-8 h), exposure increases linearly with dose, and half-life is > 24 h supporting QD dosing. Most AEs were grade 1 or 2, most commonly nausea (48%), fatigue (45%), peripheral edema, periorbital edema, vomiting (30% each), diarrhea (25%), anemia, dizziness, and lacrimation (23% each). There were no grade 4 or 5 BLU-285-related AEs, dose limiting toxicities, or discontinuations. 29 pts (all 21 PDGFRα pts) remain on treatment (duration 1-14 mo). Updated results including MTD, ct-DNA and central radiographic assessments will be presented. Conclusions: Precision targeted therapy with BLU-285 demonstrates important clinical activity in pts with both PDGFRα- and KIT-mutant GIST that is resistant to available therapies. Clinical trial information: NCT02508532.

e22516 Background: Trabectedin (T) has been shown to improve progression free survival (PFS) (4.2 vs 1.5 months, HR 0.55, p < 0.0001) in comparison to dacarbazine (D) in patients (pts) with advanced leiomyosarcoma or liposarcoma following failure of prior chemotherapy. Pts randomized to T in this phase III trial (ET743-SAR 3007) received T as a 24 hr IV infusion in either an inpatient (InP) or outpatient (OP) setting, based upon site preference. Here we report the safety, efficacy, and patient reported outcomes (PROs) of pts based on first infusion site of care. Methods: Pts were randomized 2:1 to receive T (1.5 mg/m2) or D (1 g/m2 over 20-120 min). Site of T infusion was based on institutional preference/standard of care. The site of T administration (InP vs OP) was collected for the first infusion with the assumption that site of care was unchanged for subsequent doses. Results: Of 378 pts treated with T, 100 (27%) and 277 (73%) pts received T as InP or OP, respectively. No differences were observed in PFS or overall survival (OS) by site of care (InP vs OP): Median PFS of 4.1 vs 4.2 months; HR 0.90, p = 0.49 and median OS of 14.3 vs 13.7 months; HR 0.89, p = 0.40. No difference in other efficacy endpoints between InP vs OP were observed: disease control rate (CR+PR+(SD≥18wks)) (38% vs 33%; Odds Ratio [OR] 1.22; p = 0.44) and Overall Response Rate (14% vs 8%; OR 1.76; p = 0.15)). Grade 3-4 adverse events (AEs) occurred in 87% InP vs 79% OP pts and grade 3-4 SAEs occurred in 43% InP vs 33% OP. The most common grade 3-4 AEs in both groups were increased ALT/AST, hematologic toxicity, nausea and fatigue. The incidence of grade 3-4 febrile neutropenia was similar in both groups at 5.0% InP vs 4.7% OP, as was increased blood creatine phosphokinase at 5.0% InP vs 6.1% OP, and catheter related complications of any grade at 16% InP vs 15% OP. No clinically meaningful differences were observed in PROs measured by MD Anderson Symptom Inventory scores. Conclusions: The majority of patients randomized to the trabectedin arm of the ET743-SAR-3007 Phase III study received trabectedin in the OP setting. Treatment outcomes with trabectedin suggest equivalent efficacy and safety when administered in the InP or OP setting. Clinical trial information: NCT01343277.

11058 Background: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS) typically seen in young adults accounting for < 1% of all STS. While local disease may be indolent, ES can rapidly spread and patients (pts) with distant metastasis are often resistant to systemic treatment with 1 year survival of < 50%. The defining molecular feature of ES is the absence of tumor expression of INI1, a SWI/SNF subunit member involved in chromatin remodeling. Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated tumor regressions in INI1 negative preclinical malignant rhabdoid tumors (MRT) models and phase 1 clinical activity in MRT and ES pts. The proposed mechanism of tazemetostat sensitivity is INI1 loss inducing compromised SWI/SNF activity and tumor dependence on PRC2 activity (of which EZH2 is the catalytic subunit). Preliminary phase 2 safety and efficacy of tazemetostat in ES pts is reported here. Methods: This is a phase 2 multicenter open-label single arm study of tazemetostat (800 mg po BID) in adult pts with ES whose tumors harbor evidence of INI1 loss. Pts enroll into 1 of 5 cohorts of different tumor types with INI1 loss/reduction, up to 30 pts each, using a 2-stage Green-Dahlberg design. For the ES cohort, primary endpoint is disease control rate (DCR) defined as objective response of any duration or stable disease (SD) lasting ≥32 wks. Success at stage 2 required DCR in ≥5/30 treated pts. Key secondary endpoints include safety/tolerability, ORR, PFS, OS, PK and response biomarkers e.g. H3K27me3. Results: In 31 ES pts with a median of 1 prior systemic therapy, stage 2 DCR criteria was surpassed with a RECIST confirmed PR (4 pts) and SD ≥32 wks (2 pts) observed to date. 13 pts are still on treatment therefore DCR and ORR will be updated. Tazemetostat was well tolerated with grade 1/2 fatigue (39%), nausea (26%) and vomiting (19%) as the most frequently reported AEs regardless of attribution. Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat monotherapy shows promising antitumor activity, including confirmed responses and long-term SD, with favorable safety/tolerability in ES. Enrollment has been expanded to 60 ES pts given the clinical activity described here. Clinical trial information: NCT02601950.

TPS11080 Background: Activating mutations in the kinase domain of PDGFRA account for 10-15% of GIST. The most common PDGFRA mutation reported is D842V, which is known to confer resistance to imatinib and sunitinib. Currently, there is no approved treatment for GIST patients carrying such mutation. Cassier PA et al. showed that patients with D842V mutated GIST had a short median progression free survival (PFS) of 2.8 months with first line imatinib and 2.1 months with second line (2012 Clin Cancer Res). Crenolanib is a highly selective PDGFRA and FLT3 inhibitor with nanomolar activity against PDGFRα D842V mutation. In a previous dose-finding study, crenolanib showed a 31% clinical benefit rate with 2 pts achieving PR and 3 pts maintaining SD (total evaluable: 16 pts) in heavily pretreated GIST patients harboring the PDGFRA D842V mutation. In this study, 35% patients stayed on study for at least 7 months despite 80% patients having progressed after prior imatinib (15 pts), sunitinib (7 pts), dasatinib (5 pts), sorafenib (4 pts), nilotinib (2 pts), and regorafenib (2 pts). Therefore, a phase III trial has been initiated to further confirm the clinical activity of crenolanib in patients with PDGFRA D842Vmutation. Methods: This randomized phase III study will enroll adult subjects with histologically or cytologically confirmed advanced or metastatic GIST with a PDGFRA D842V mutation. Prior treatment with TKI is allowed. Approximately 120 subjects will be randomized in a 2:1 ratio to receive either crenolanib 100 mg or matching placebo orally 3 times daily in combination with best supportive care. Randomization will be stratified by prior tyrosine kinase inhibitor exposure and ECOG performance status. The primary objective is PFS; key secondary objectives include OS. A formal interim analysis is planned after approximately 50 subjects have met the primary outcome. This study is already opened in the US, France, Norway, and Poland, and will soon be opened in Germany, Italy, Spain, UK and Asia. NCT02847429; EudraCT: 2015-000287-34 Clinical trial information: NCT02847429.

23 Background: The success of immunotherapy has raised new issues regarding the selection of patients, design of combination strategies, and sequencing of various regimens. Sarcomas have poor outcomes in the metastatic setting but may be amenable to immune therapies. However, we currently have limited knowledge of the immunologic profiles of different soft tissue sarcoma (STS) subtypes. Methods: We identified patients with the relatively common STS subtypes: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS) and liposarcoma. Formalin fixed paraffin embedded (FFPE) tumor samples from 81 patients underwent gene expression analysis, immunohistochemistry for PD-1 and PD-L1, and sequencing of the T cell receptor Vβ region. Differences in liposarcoma subsets were also evaluated. Results: UPS and LMS had high expression levels of genes related to antigen presentation and T cell infiltration. UPS had higher levels of PD-L1 (p ≤ 0.001) and PD-1 (p ≤ 0.05) on IHC. UPS also had the highest T cell infiltration based on TCR sequencing, significantly more than SS, which had the lowest (p ≤ 0.05). UPS and LMS both had higher clonality compared with SS and liposarcoma (p ≤ 0.05). A model adjusted for STS histologic subtype found that for all sarcoma T cell infiltration and clonality were highly correlated with PD-1 and PD-L1 staining levels (p ≤ 0.01). Conclusions: In a model adjusted for sarcoma histologic subtypes, T cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression, consistent with the emerging view of tumor immunity that highly inflamed tumors acquire inhibitory ligands to evade tumor-specific T cells. UPS, which is a more highly mutated STS subtype, provokes a strong immune response evidenced by multiple inflammatory features suggesting that it may be well-suited to checkpoint inhibitor based approaches. SS and liposarcoma subsets are less highly mutated but do express immunogenic self-antigens therefore strategies to improve antigen presentation and T cell infiltration may be valuable for allowing immunotherapeutic success in these tumor types.

11061Background: T is recently approved in the US for treatment of advanced LMS or LPS after prior chemotherapy failure based on results from a randomized, phase-3 study (Demetri et al, 2015, J Cli...

3093Background: Immune approaches that stimulate specific anti-tumor cytotoxic T cells (CTLs) can have single agent activity, be synergistic with check point inhibitors (CPIs) and enhance adoptivel...

11033Background: Treatment of patients with metastatic Ewing sarcoma (ES) remains a challenge. Pre-clinical studies and small retrospective series, mainly including pediatric patients, have demonst...

11017Background: Tumor associated macrophages (TAM) are critical for immune evasion in many tumors. We hypothesized that combining G100, a TLR4 agonist that stimulates innate immunity and increases...

10501 Background: Options for patients (pts) with unresectable/metastatic STS are limited. While Dox is standard of care, Dox combinations have yet to improve overall survival (OS) over Dox alone. Olaratumab (IMC-3G3), a fully human monoclonal antibody, selectively binds PDGFRα (a signaling pathway implicated in STS), blocks ligand binding, and enhances Dox activity in preclinical sarcoma models. Methods: We conducted a phase Ib, open-label, randomized phase II study of Dox ± olaratumab in unresectable/metastatic STS (NCT01185964). Pts received Dox (75 mg/m2 Day 1) with (Arm A) or without (Arm B) olaratumab (15 mg/kg Days 1 and 8, every 21 days), a dose and schedule confirmed safe in phase Ib, for up to 8 cycles. In Arm A, olaratumab monotherapy continued after Dox until disease progression; in Arm B, pts could cross over to olaratumab at progression. The primary endpoint was progression-free survival (PFS; target hazard ratio [HR] = 0.67, 80% power, α = 0.2) with OS as a secondary endpoint. Results: Of 1...

10516 Background: Belinostat is a novel histone deacetylase (HDAC) inhibitor. This study assessed the MTD and DLTs of the combination of belinostat and doxorubicin in solid tumours (phase I) and ef...

10545 Background: Patients (pts) with metastatic Soft Tissue Sarcoma (STS) are known to have poor outcomes with median overall survival (OS) reported to be circa 12 months. Recent publications have...

3021 Background: Generation of tumor-specific cytotoxic T cells (CTLs) in vivo is a major goal of cancer immunotherapy. LV305 is a replication-incompetent, integration-deficient, hybrid viral vecto...

e21516 Background: Doxorubicin (Dox.) (alone or in combination) is the standard first line therapy for metastatic soft tissue sarcoma (STS). Cardiotoxocity is an important complication of dox., and is often defined as left ventricular ejection fraction (LVEF) 10%. Studies in patients treated with high dose chemotherapy have suggested that elevated troponin levels predict the development of cardiotoxicity. However, conflicting data exists for conventional dose chemotherapy. We aimed to evaluate the utility of troponin to predict cardiotoxicity in metastatic STS patients treated with dox. Methods: Over 18 months, all patients with metastatic STS receiving single agent dox. received echocardiograms and serum troponin I (TnI) levels at baseline and following cycles 2, 4 and 6. TnI was measured using the Beckmann Coulter Access 2 assay with a normal range of < 40 ng/L. Results: 41 patients (28 female, 13 males), median age 58 years, were studied. 11 (27%) had cardiac risk factors. Median num...

10503 Background: This phase III multicenter trial compared T with D in pts with advanced LPS or LMS previously treated with an anthracycline and at least one additional systemic therapy. Methods: ...

10520 Background: Recurrence after resection of metastatic sarcoma is common. The gangliosides GM2, GD2 and GD3 are strongly expressed on many sarcomas. The generation of anti-ganglioside antibodie...

e21502 Background: Leiomyosarcoma (LMS) of bone is a very rare sarcoma subtype. These tumors are managed akin to osteosarcoma, with neoadjuvant chemotherapy followed by surgery. The precise role of chemotherapy remains to be defined. Methods: Patients treated with primary bone LMS at the University of Washington between 2002 and 2012 were included. Patients with high grade tumors were treated with neoadjuvant chemotherapy and surgery; whereas those with low grade tumors were treated with surgical resection alone. Chemotherapy consisted of doxorubicin and ifosfamide x 2 cycles. Treatment details included: initial treatment (surgery versus chemo), surgical and pathological margins, and timing of chemotherapy. Follow-up data included: time to local recurrence, time to metastasis, time to last follow up if alive, or time to death. Results: Ten patients were identified, 4 male and 6 female. Median age at diagnosis: 52 years (range 29 - 91). The primary site was the distal femur in 5 patients, and the hemipelvis, acetabulum, proximal femur, distal clavicle and mid-shaft of femur in 1 patient each. Median tumor size at diagnosis was 8 cm. Five were high-grade tumors; 3 were intermediate and 2 were low grade. Four of 10 patients received neoadjuvant chemotherapy, with the following histological response; 70%, 30%, 15% and

535 Background: RCB and Ki67 after neoadjuvant chemotherapy have each been shown to predict long-term outcome. Their combined use might provide greater prognostic information. RCB requires collection of data beyond that in routine pathological work-up of residual disease, which may not be required when Ki67 is added. Aims: (i) To test the hypothesis that combining Ki67 and RCB as the residual proliferative cancer burden (R-P-CB) provides significantly more prognostic information than either alone. (ii) To determine if a simplified algorithm integrating Ki67 and standard characteristics of residual disease can provide as much information. Methods: Cases at the Royal Marsden Hospital between 2002-2010 were identified and residual disease assessed. The primary endpoint of the study was time to recurrence. The primary analysis compared the prognostic information from Ki67, RCB and R-P-CB. Analyses employed a Cox proportional hazards model. Prognostic indices (PIs) were also created adding Ki67, grade and ER to the RCB and AJCC staging. Leave-one-out cross validation was used to reduce bias. The overall change in chi-square (ΔX2) of the best model for each index was used to compare the prognostic ability of the different indices a ΔX2 of more than 3.84 indicates statistical significance. Results: A total of 222 evaluable patients were included in the study, median age was 50 with a median follow up of 60 months. The addition of Ki67 improved the prognostic power of all indices. The R-P-CB (ΔX2=69.5) was significantly more prognostic than the RCB alone (ΔX2=35) and Ki67 alone (ΔX2=41.4). A novel proliferative residual cancer index (PRECI) using post-treatment values of T size, number of involved lymph nodes, grade, ER status (±) and Ki67 gave ΔX2=81.1 and performed similarly to a model including the RCB, Ki67, ER and grade (ΔX2=80.2). Conclusions: Addition of Ki67 to RCB improved prediction of long-term outcome. In this study, a novel index the PRECI provided as much prognostic information as a more complex assessment involving RCB and warrants further investigation for estimating post-neoadjuvant risk of recurrence.

10011^ Background: We previously reported a regimen of epirubicin/ifosfamide (E/I) and hypofractionated radiation (RT) followed by surgery and postoperative E/I. We hypothesize that S + CRT is safe and augments activity through anti-angiogenic mechanisms. We performed dynamic contrast-enhanced MRI using shutter speed pharmacokinetic analysis (SSM DCE-MRI) to assess preoperative therapy effect. Methods: Subjects with >5 cm, grade 2-3 extremity STS were treated in cohorts of escalating S dose using a 3+3 design based on dose-limiting toxicity (DLT) during the first 8 weeks. Daily S was initiated 14 days prior to E/I (E 30 mg/m2/day days 1-3 and I 2.5 g/m2/day days 1-3 every 21 days for 3 pre- and 3 postoperative cycles). 28 Gy preoperative RT was administered in 8 fractions during cycle 2 (E omitted). Primary objective was to determine maximum tolerated dose (MTD). DCE-MRI was performed at baseline, after 2 weeks S, and prior to surgery. Results: 16 subjects were enrolled. Histologies included pleomorphic (5), synovial (5), liposarcoma (3), other (3). All were extremity (12 lower, 4 upper) tumors. Median tumor size was 11.7 cm. The MTD of S was 400 mg daily (see table). Most common grade 3/4 adverse events among all dose levels were neutropenia (94%), anemia (75%), hypophosphatemia (69%), thrombocytopenia (56%), neutropenic fever/infection (50%), and hypokalemia (31%). 38% developed wound complications requiring surgical intervention including amputation in 1 subject. 44% had >95% histologic necrosis at surgery. No subjects have recurred with median follow-up of 15 (6-27) months. 8 subjects underwent DCE-MRI. Changes in SSM DCE-MRI biomarkers after 2 weeks S correlated with histologic response (R2=0.71). Conclusions: The addition of S to CRT is feasible with promising activity that warrants further investigation. Rate of wound complications is similar to other reports of preoperative radiation. SSM DCE-MRI detected changes in tumor perfusion after only 2 weeks of S and may prove useful to assess early drug effect in STS. [Table: see text]

TPS10099 Background: PDGFRα is a receptor commonly overexpressed in STS. Olaratumab is a fully human IgG1 MAb which specifically binds to human PDGFRα and blocks PDGFR-mediated signaling pathways. Olaratumab demonstrated significant tumor inhibition as a monotherapy and in combination with standard chemotherapy in preclinical human sarcoma xenograft models. A Phase 1b/2 clinical trial for patients with advanced or metastatic STS is currently enrolling patients in 9 sites across the United States; approximately 45 patients have been randomized. Methods: In Phase 1b, patients received olaratumab (15 mg/kg) via intravenous infusion on Days 1 and 8 of each 21-day cycle and D (75 mg/m²) 1 hour after olaratumab on Day 1. Phase 1b was completed without encountering dose-limiting toxicities; enrollment into Phase 2 has begun. The primary endpoint of the Phase 2 portion is to compare progression-free survival in patients with advanced STS when treated with D plus olaratumab versus D alone. Planned enrollment goal for Phase 2 is 130 patients. Patients are required to be ≥ 18 years old with ECOG 0-2, have appropriate organ function and histologically confirmed, measurable, and advanced STS. There is no restriction on the number of prior therapies. Patients are randomized 1:1 to either D plus olaratumab (Arm A) at same dose/schedule as in Phase 1b or D alone (Arm B). All patients can receive dexrazoxane. Upon completion of 8 cycles, patients in Arm A continue with olaratumab monotherapy. Patients in Arm B who develop disease progression during or after treatment can subsequently receive olaratumab monotherapy. Patients are stratified to treatment arms according to PDGFRα expression (positive vs. negative), number of previous lines of treatment, sarcoma subtype, and ECOG performance status. Response assessment occurs every 6 weeks. Exploratory analyses include biomarkers of olaratumab pharmacodynamic activity including PDGF ligands, PDGFR downstream molecules, VEGF, and changes in vascularity of tumor specimens.

10086 Background: In patients with advanced GIST, imatinib trough levels have been associated with a lower rate of clinical benefit. Anecdotal observations have suggested that commencing treatment with imatinib may be associated with an increase in red blood cell size as measured by MCV and MCH, indicating the effect of imatinib on KIT signalling in the bone marrow. Methods: In this retrospective review we examined a possible connection between changes in MCV and MCH after the first 3 months (mo) of treatment with imatinib and progression-free survival (PFS). Data for patients with inoperable advanced or metastatic GIST treated between 2000 and 2011 were available for analysis. Patients were categorised in quartiles according to the distribution of the percentage of change of MCV and MCH between start of imatinib (baseline) and 3 (+/- 0.5) mo (ratio %=MCV change at 3 mo/MCV at baseline). PFS curves were plotted using the Kaplan-Meier method and compared using the log rank test. Results: One hundred and thirty patients were eligible for analysis and the demographics were: male:female 84:46, median age at presentation: 60.5 (23.5-86.5) years, commonest primary tumour sites: stomach (72/130) and small bowel (44/130), commonest metastatic site: liver (76/130). In the patients with a 10% or over increase in MCV (p75-p100) at the 3 mo (+/-0.5) time point a significantly longer PFS was observed compared to those with a smaller magnitude of change (PFS of 37.1 mo vs 24.3 mo, p=0.032). A similar trend although not statistically significant was observed in patients with MCH of 15% or over (p75-p100) with PFS of 34.0 mo vs 25.8 (p=0.125). The two parameters (MCV and MCH) showed a high correlation of percentage change (r2=0.85). The patients with a 10% MCV increase and /or 15% MCH increase (total=40) showed a significantly longer PFS (34.0 mo) compared to those with lower percentage change (PFS= 24.3) p=0.035. Conclusions: Simple laboratory parameters may be indicators of imatinib pharmacokinetics and may therefore be used as surrogate markers of clinical outcome. Larger prospective studies are required to confirm the results of this study.

10039 Background: Ifosfamide (IFO) has recognised activity in soft tissue sarcomas. There is evidence for improved cytotoxicity and tolerability utilising a prolonged 14 day infusional outpatient regimen compared with the standard 3-day regimen (Loeffler et al 1990). We undertook a retrospective review of all patients treated with this regimen from September 2008 - December 2011 to determine toxicity and treatment response. Methods: Pts. were identified from our database and demographics, histological subtype, toxicity and survival outcomes were collected. IFO was given via central venous access using 2 x 7 day pumps at 1g/m2/day with mesna for 14 days q 4 weekly. Oral sodium bicarbonate was used to maintain alkaline urine with oral mesna for haematuria, and thiamine for symptoms of encephalopathy as required. Results: 29 patients (pts), with advanced sarcoma, median age 56 years (27-76 yrs), 14F 15 M, median number of cycles = 1 ( 1-9). At baseline: PS 0=1, 1=24, 2=4. 18 pts had de-differentiated liposarcoma (D-LPS), 6 synovial sarcoma, 5 had other subtypes. 12 pts received only 1 cycle, with 5 stopping due to encephalopathy. Ten patients developed encephalopathy, 9 occurring in cycle 1, other toxicity was tolerable, with Gr 2-3 nausea (15 pts) and vomiting (9pts) and only 2 Gr 3 episodes of myelotoxicity for all cycles. 4 patients achieved PR, (2 with D-LPS and 2 with Synovial sarcoma) 11 pts. had SD. Median PFS was 19 months and OS was 12.5 months. 2 pts. with D-LPS had a sustained prolonged response of 15 and 16 months. Conclusions: Infusional IFO is generally well tolerated; however a significant incidence of neurotoxicity was seen. Pts. with D-LPS demonstrated best response to treatment, a sarcoma subtype that has previously failed to respond to systemic therapy. This regime warrants further investigation.

10000 Background: Pts with sarcomas, a family of >70 types of cancer, have limited options once cytotoxic agents fail. Brivanib (B) is an oral once daily selective dual inhibitor of FGF and VEGF signaling currently in phase III. Data from a phase II trial were analyzed to evaluate the potential utility of biomarkers and STS subtypes in predicting response to B. Methods: Pts aged ≥18 y with unresectable STS and no other treatment options received open-label B 800 mg qd for a 12-wk lead-in period and were assessed by CT/MRI. Pts with RECIST response continued on open-label B, those with progressive disease (PD) went off study. Pts with stable disease (SD) were randomized 1:1 to B or placebo (P), stratified by FGF2 expression (IHC + or -), until PD or unacceptable toxicity. Pts with PD on P could crossover to resume open-label B. The primary endpoint was PFS for B vs P in FGF2+ pts; secondary endpoints included ORR, DCR (ORR+SD), and exploratory biomarkers. Results: Of 251 pts (52% with ≥2 prior systemic reg...

10087 Background: Ifosfamide (IFO) has recognised activity in soft tissue sarcomas (STS). There is preliminary evidence for improved cytotoxicity utilising a prolonged 14 day infusional regimen of ...

10098 Background: Clear cell sarcoma is a rare soft tissue sarcoma subtype associated with the characteristic translocation t(12;22)(q13;q12). There have been few studies documenting the response r...

611 Background: NF-kB is a potential therapeutic target in breast cancer and other tumor types. However, studies assessing its significance in a clinical setting are as yet limited. The aim of this study was to evaluate clinicopathological associations and predictive value of the transcription factor NF-kB in a large series of breast cancer patients that received neoadjuvant systemic treatment. Methods: A retrospective search of a prospectively maintained database was performed to identify patients. Immunohistochemistry was employed to asses the p65 subunit of NF-kB using nuclear staining, as a surrogate of activation. Results: Nuclear NF-kB expression (n = 133) was found in 26.3% (n = 35) of cases. Nuclear NF-kB staining was associated with high histological grade (p = 0.05), ER negativity (p = 0.01) and high Ki67 index (p = 0.002). Patients with nuclear NF-kB staining had a higher pathological complete response (pCR) rate compared to those without (26.5% vs. 6.0% respectively, p = 0.004); there were no ...

2530 Background: OSI-906 is a potent inhibitor of IGF-1R and IR tyrosine kinase activity. Increased IGF-1R activity is observed in human malignancies and implicated in resistance to chemotherapy. M...

10519 Background: Aggressive fibromatosis (AF) or desmoid tumors are monoclonal proliferations which are locally invasive but do not metastasise. Sporadic tumors are usually associated with mutations in the beta-catenin gene CTNNB1whereas those occurring in the context of familial adenomatous polyposis usually have inactivating mutations in APC. Histologically they are characterised by nuclear expression of beta-catenin. When surgery and radiotherapy are not applicable or fail to control the disease, systemic treatment with anti-oestrogens, non steroidal anti-inflammatory drugs (NSAIDs) and chemotherapy can be used. A variety of regimens are reported to have activity including methotrexate/vinblastine and doxorubicin/dacarbazine. Recent reports indicate that single agent pegylated liposomal doxorubicin (Caelyx, C) is also effective. Methods: Ten patients with AF received C between June 2006 and December 2008. C was administered intravenously at 50 mg/m2 over 1 hour every 4 weeks. Results: The female/male ratio was 9:1 and the median age at presentation was 39.5 years (range 18–53). All patients had progressive fibromatosis. Fifty percent had previously been treated with surgery/radiotherapy or both. All but one had previous systemic therapy which comprised tamoxifen/toremifene (6), NSAIDs (1), chemotherapy (1) and imatinib (1). C was well tolerated with mucositis (6/10), palmar-plantar erythema (4/10) and fatigue (2/10) being the main toxicities. A dose reduction to 40 mg/m2 was required in 50% of cases hence the optimal dose lies between 40 and 50 mg/m2. One patient is currently receiving treatment and is too early to assess. For the nine patients who have completed treatment the median number of C cycles was 6 (range 4–6). Objective response according to RECIST was achieved in 4/10 patients and in 5 patients the best response was stable disease. Clinical benefit (pain relief, improved mobility) was observed in all patients. The duration of response ranged from 4 to 28 months. Conclusions: This is the largest series of patients with AF receiving C presented to date. C as single agent therapy has acceptable toxicity and highly promising activity in unresectable AF and may provide long term clinical benefit in some patients. No significant financial relationships to disclose.