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11516Background: T-VEC is an oncolytic immunotherapy derived from HSV type-1 that is modified to selectively replicate within tumors and produce GM-CSF. Pembrolizumab (P) demonstrated activity in s...

Neoplasms of histiocytic and dendritic cell origin, including follicular dendritic cell sarcoma (FDCS), histiocytic sarcoma (HS) and interdigitating dendritic cell sarcoma (IDCS), are extremely rare, and data on their natural history and treatment outcomes are sparse. We evaluated the impact of surgery, radiation and systemic therapies on overall survival (OS).We conducted a retrospective chart review of patients with FDCS, IDCS and HS treated at Memorial Sloan Kettering Cancer Center between 1995 and 2014.We identified 31, 15 and 7 patients with FDCS, HS and IDCS, respectively. Median age was 48.7, 42.3 and 58.8years for FDCS, HS and IDCS, respectively. Only a slight disparity in gender distribution existed for FDCS and HS; however, IDCS predominantly affected males (6:1). The most common sites of presentation were abdomen and pelvis (42%), extremities (33%) and head and neck (57%) for FDCS, HS and IDCS, respectively. At diagnosis, 74%, 40% and 86% of patients presented with localised disease in FDCS, HS and IDCS, respectively. Patients with localised disease had significantly improved OS than those with metastatic disease in FDCS (P=0.04) and IDCS (P=0.014) but not in HS (P=0.95). In FDCS and HS, adjuvant or neo-adjuvant therapy was not associated with improved OS compared with observation. In IDCS, surgery alone provided a 5-year overall survival rate of 71%.Adjuvant or neo-adjuvant treatment in FDCS and HS did not affect OS. Patients with IDCS had an excellent outcome with surgery. In the metastatic setting, chemotherapy and small molecule inhibitors may provide benefit.

Gemcitabine (G) and docetaxel (D) are commonly used to treat recurrent/metastatic soft tissue sarcoma. This study tested the hypothesis that outcomes would be improved by addition of bevacizumab (B). The initial design was randomized double-blind trial of G + D + B versus G + D + placebo. Due to slow accrual this was modified to single-arm open-label G + D + B. Eligible patients had diagnosis of leiomyosarcoma, pleomorphic undifferentiated sarcoma, pleomorphic liposarcoma, or angiosarcoma. Treatment was B 15 mg/kg on d1, G 900 mg/m2 on d1 and d8, and D 75 mg/m2 on d8, q21d. Primary endpoint was progression-free survival (PFS) at 6 months and would be met if ≥17 patients were progression-free at 6 m. Secondary endpoints are response rate, PFS at 3 m, overall survival, and toxicity. Of 44 patients enrolled, 35 were treated with GDB and evaluable for safety and efficacy. Median age was 55, 50% male, most ECOG 0. Toxicity is mostly myelosuppression with one deep vein thrombosis and one small bowel perforation possibly related to B. There were 17 partial responses (49%) by RECIST 1.1. Among 35 patients, the number who remained on study and progression-free was 24 at 3 m and 15 at 6 m. 9 withdrew prior to 6 m for reasons other than toxicity or progression. PFS at 6 m was 65% (95% CI: 51–85%). The primary endpoint of 6 m PFS was not met due to censoring of patients who withdrew. However PFS at 3 m (76%) was promising and response rate was higher than expected from G + D.

Background In a randomized phase III trial, pemetrexed plus cisplatin was associated with improved survival compared with cisplatin alone for patients with malignant pleural mesothelioma (MPM). However, there are limited data available on the efficacy of these and other chemotherapy regimens in patients who have received previous systemic chemotherapy. To gather additional efficacy and safety data of pemetrexed/cisplatin and pemetrexed alone in previously treated patients, we examined patients treated on the Eli Lilly and Company expanded access program (EAP). Patients and Methods Patients with malignant mesothelioma were enrolled in this trial. Of 1056 patients receiving at least one dose of the study drug, 187 (17.7%) were previously treated patients with MPM. Patients were treated every 21 days with pemetrexed 500 mg/m 2 alone ( n = 91) or in combination with cisplatin 75 mg/m 2 ( n = 96) for a maximum of six cycles. All patients received folic acid and vitamin B12 supplementation and steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmaco-vigilance database for all patients enrolled in the EAP. Results Median age of the previously treated pleural mesothelioma subset was 66 years (range, 27–87 years). Based on 153 evaluable patients (a subset of the larger intent-to-treat population of 187), the overall response rate was 32.5% for pemetrexed and cisplatin and 5.5% for pemetrexed alone. The disease control rate (response rate + stable disease) was 68.7% for pemetrexed and cisplatin and 46.6% for pemetrexed alone. Median survival was 7.6 months for pemetrexed plus cisplatin (67% censored) and 4.1 months for pemetrexed alone (55% censored). The most commonly reported serious adverse events in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). Conclusions The data from this EAP study suggest that patients with previously treated MPM can benefit from treatment with pemetrexed alone or in combination with cisplatin. The treatment is associated with acceptable toxicity.

BACKGROUND: To date, few large studies have been reported of patients with peritoneal mesothelioma, and treatment of this disease has been largely extrapolated from the treatment of pleural disease. Hence, it was considered important to study and report on this specific patient population. Before the regulatory approval of pemetrexed, an expanded access program (EAP) provided access to eligible patients with malignant pleural or peritoneal mesothelioma. PATIENTS AND METHODS: Patients received pemetrexed 500 mg/m 2 alone or in combination with cisplatin 75 mg/m 2 once every 21 days for ≤ 6 cycles. All patients received folic acid, vitamin B 12 , and steroid prophylaxis. Serious adverse events (SAEs) were compiled in a pharmacovigilance database, which included all patients in the EAP with pleural or peritoneal mesothelioma. From June 12, 2002 to February 18, 2004, 1056 patients with malignant mesothelioma were enrolled and received ≤ 1 dose of treatment at 462 sites in the United States. Of these patients, 98 (9.3%) had peritoneal mesothelioma (57 previously treated, 38 chemotherapy-naive, and 3 with missing data). RESULTS: Response data were available for 73 patients (43 previously treated, 28 chemotherapynaive, and 2 not classified), indicating response rates of 23.3% for previously treated patients (0 complete responses [CRs], 10 partial responses [PRs], 21 cases of stable disease [SDs], 12 cases of progressive disease [PDs]) and 25% for chemotherapy-naive patients (3 CRs, 4 PRs, 12 SDs, and 9 PDs). Median survival was 13.1 months for previously treated patients and has not been reached for chemotherapy-naive patients. The most commonly reported SAEs for the total EAP were dehydration (7.2%), nausea (5.2%), and vomiting (4.9%). CONCLUSION: Pemetrexed with or without cisplatin had a favorable safety profile, and the disease control rate (CR + PR + SD) of 71.2% in the subset of patients with peritoneal mesothelioma indicated activity in this patient population.

The cancer-testis antigen NY-ESO-1 is one of the most promising candidates for generic vaccination of cancer patients. Here we analyzed the CD8+ T cell response to a NY-ESO-1 peptide vaccine composed of the two previously defined peptides 157-165 and 157-167, administered with GM-CSF as a systemic adjuvant. The NY-ESO-1 peptide vaccine elicited a CD8+ T cell response directed against multiple distinct epitopes in the 157-167 region, as revealed by using A2/peptide multimers incorporating overlapping A2 binding peptides in this region. However, only a minor fraction of the elicited CD8+ T cells, namely those recognizing the peptide 157-165 with sufficiently high functional avidity, recognized the naturally processed target on NY-ESO-1+ tumor cells. In contrast, the majority of peptide 157-165–specific CD8+ T cells exhibited lower functional avidity and no tumor reactivity. In addition, vaccine-elicited CD8+ T cells specific for other overlapping epitopes in the 157-167 region failed to significantly recognize NY-ESO-1–expressing tumor targets. Thus, because of the complexity of the CD8+ T cell repertoire that can be elicited by vaccination with synthetic peptides, a precise definition of the targeted epitope, and hence, of the corresponding peptide to be used as immunogen, is required to ensure a precise tumor targeting.

11039 Background: Preclinical studies suggest that imatinib resistance (IR) in GIST can be mediated by MAP-kinase activation via FGF signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR inhibitor in combination with imatinib, is cytotoxic and superior to imatinib alone, or imatinib in combination with MEK-inhibition. In GIST with FGF signaling, the combination of BGJ398 and imatinib may provide a mechanism to overcome IR. Methods: This phase Ib study of BGJ398 in combination with imatinib was performed in patients (pts) with imatinib resistant advanced GIST. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose. Two treatment schedules were evaluated incorporating imatinib 400mg daily continuously in combination with (A) BGJ daily 3 wks on, 1 wk off or (B) BGJ daily 1 wk on, 3 wks off. Response was evaluated by RECIST and CHOI every 8 wks x4 and then every 12 wks. Results: 16 pts enrolled. Median age 54 (range: 44-77), 81% male, median prior therapy 4 [range: 2-6, 13/16 pts had ≥ 3 prior therapies (81%)]. 12 pts received treatment on schedule A [dose level (DL)1 (BGJ 75mg), n = 6; DL-1 (BGJ 50mg), n = 3; DL-2 (BGJ 25mg), n = 3]: 3 DLTs (myocardial infarction, grade (G)4 CPK elevation, G3 ALT elevation) were observed on schedule A at DL1, hyperphosphatemia (on target effect) was not observed raising concern for therapeutic efficacy at the maximum tolerated dose. Following protocol amendment that allowed an alternative dosing schedule, 4 pts enrolled on schedule B [DL1 (BGJ 75mg), n = 3; DL2 (BGJ 100mg), n = 1]: one DLT occurred (G3 intra-abdominal hemorrhage) at DL2. The most common non-DLT G3/4 toxicity was HTN (2/16pts) and G2 toxicity was prolonged QTc interval (3/16pts). Of the 12 pts with evaluable CT scans, stable disease (SD) was the best response observed in 7 pts by RECIST and 9 pts by CHOI. 3pts achieved SD for > 6 months. 2 pts remain on study at data cut-off (range: 1 – 67 wks). Median progression free survival is 8 weeks. Pharmacokinetic analysis of imatinib and BGJ is forthcoming. Conclusions: In heavily pre-treated pts, durable disease control was observed in 3/16 pts. This signal of efficacy suggests that further evaluation of FGF signaling in the development of IR is warranted. Clinical trial information: NCT02257541.

11010 Background: The majority of GISTs harbor activating mutations in KIT or PDGFRα but the clinical relevance of other genomic alterations is unknown. We sought to determine the clinical impact of performing routine NGS and to describe the molecular landscape in GIST. Methods: From April 2014 to August 2016, 177 patients (pts) consented to an IRB-approved protocol. Tumor and matched normal samples were prospectively analyzed in a CLIA-compliant laboratory, with MSK-IMPACT, a NGS assay of up to 468 cancer-associated genes. Results: 191 samples were analyzed. NGS was most often performed in the setting of advanced disease (n = 108 (57%)). The primary tumor was most commonly tested (n = 120 (63%)). NGS guided clinical management in 79% (n = 150) of cases [matched therapy (MT) offered, n = 120/150 (80%); MT not offered, n = 24/150 (16%)]. In 25/41 cases (61%) where NGS did not influence management, treatment was not indicated because the GISTs were low risk. Most samples had ≤ 3 mutations (muts) (range: 0-17). Actionable muts were identified in 155/191 samples (81%). These included muts in KIT, PDGFRα and BRAF [oncoKB stratification: level 1 (84%), 2A (13%), 2B (2%), 3A(1%)]. 33/177 pts did not have a KIT/ PDGFRα mut [SDH deficiency, n = 15 (45%), NF1, n = 10 (30%), BRAF, n = 1(3%), NF1&BRAF, n = 1 (3%)]. 5pts had quadruple wild type GIST. Most GISTs had at least one genetic alteration in a non-driver allele (74%, n = 141/191)[frequently mutated genes in KIT exon 11 driven i) primary tumors include TP53, MAX, MLL2, SETD2, PIK3CA, TSC1; and ii) metastatic tumors include RB1, SETD2, PTEN, ANKRD11, TP53, TSC1]. CDKN2A deletion was the most common copy number alteration identified in KIT driven GIST and occurred most often in metastatic samples (with and without co-occurring, secondary KIT muts) and those with high mitotic rate. Conclusions: NGS of GIST informs clinical management in the majority of pts through the identification of muts in canonical driver genes. NGS also identifies a high prevalence of tumor-specific genetic alterations in non-canonical driver genes. These genes function in multiple pathways including intracellular signaling, chromatin remodeling, proteasomal degradation and cell cycle regulation.

e22518 Background: IFOS is commonly used in the treatment of met sarc. IFOS has been reported to cause encephalopathy in 5 - 30% of pts. Potential risk factors for IFOS-induced encephalopathy (IIE) include female gender, older age, route of administration of IFOS, low serum albumin, existence of pelvic disease and renal failure. Unfortunately, the majority of the data surrounding potential risk factors is from heterogeneous cohorts. Methods: The purpose of this single-center retrospective analysis was to identify risk factors for developing IIE in a homogenous cohort of met sarc pts treated at MSKCC between 1/2010 and 5/2015. Logistic regression was used to examine the univariate effect of baseline and treatment variables. Variables significant at the 0.05 level were entered into a multivariate model. Results: A total of 328 met sarc pts with a median age of 51 years were analyzed. Thirty-four pts (10%) developed IIE. Of those 34 pts, 88% developed encephalopathy with the first or second cycle of IFOS. Age at the time of treatment (p = 0.0037), low serum albumin (p < 0.0001), increased serum alkaline phosphatase (p = 0.0022), liver met disease (p = 0.0011) and more than 3 met sites at time of IFOS dose (p = 0.0008) were all identified as risk factors by univariate analysis. Only low serum albumin (p < 0.0001, odds ratio = 0.33) and more than 3 met sites at time of IFOS dose (p = 0.0068, odds ratio = 2.47) maintained statistical significance after multivariate analysis. Conclusions: To our knowledge, this is the largest retrospective analysis of risk factors for IIE in the met sarc population. This analysis identified low serum albumin and more than 3 met sites at time of IFOS as predictors of IIE. Our data would suggest that clinicians considering the option of IFOS in met sarc pts should give particular attention to these predictive risk factors when making their treatment decisions.

11001 Background: The utility of NGS in management of sarcoma pts remains undefined. Methods: We retrospectively analyzed the NGS profile of patients who were sequenced using a panel of 405 cancer-related genes in DNA and 265 genes rearranged in RNA. Diagnostic and therapeutic implications of mutations (mut) were evaluated through published literature (OncoKb.org, Pubmed). An algorithm was applied to determine germline mut. Following IRB approval, we evaluated the clinical outcomes of pts who underwent NGS at MSKCC. Results: From 2012–2016, 5635 pts worldwide with 56 histologies were tested. Median age of 52 yrs ( < 1-88), 52% females and sarcoma NOS (n = 858) was most frequent. Tumors were sequenced to a mean coverage of 634X; 1165 fusions and > 60,000 mut were found. Mut suspicious for germline defects were seen in 542 pts (9.6%) in known and novel genes ( BRCA, ARID1, FANC). Tumor mutational burden was 2.5/Mb (0–329) and glomus tumors and EHE had the highest and lowest mut, respectively. 16% and 7% of pts had treatment-linked alterations (TLA) known to respond to an FDA approved or study drug, respectively. 42% of pts had TLA eligible for NCI-MATCH, ASCO-TAPUR or other studies. Novel TLA include AKT, ESR1, BRCA, NTRK, PTCH1, SMARCB1 and others. Of the 107 MSKCC pts with clinical data, 60/107 (57%) had at least one TLA, of which 31 (30%) enrolled on a matched trial and 26 pts were ineligible or lacked access to trials. Partial/complete responses were seen with inhibitors to NTRK, IDH1, BRAF, PI3K/mTOR, MDM2, SMARCB1 and others. NGS changed the initial pathology diagnosis and treatments in 5% pts (e.g. LMS to liposarcoma, clear cell to melanoma). Resistance mutations averted futile therapies in 5% pts (e.g. Rb loss and palbociclib in liposarcoma). Conclusions: Our data suggests that NGS has a significant impact in aiding diagnosis and selecting matched therapies in sarcoma. Suspected germline aberrations, while intriguing, needs further validation.

Immune-based therapies for cancer are generating substantial interest because of the success of immune checkpoint inhibitors. This study aimed to enhance anticancer immunity by exploiting the capacity of dendritic cells (DCs) to initiate T cell immunity by efficient uptake and presentation of endocytosed material. Delivery of tumor-associated antigens to DCs using receptor-specific monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits robust antigen-specific immune responses in preclinical models. DEC-205 (CD205), a molecule expressed on DCs, has been extensively studied for its role in antigen processing and presentation. CDX-1401 is a vaccine composed of a human mAb specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase 1 trial assessed the safety, immunogenicity, and clinical activity of escalating doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8) and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies refractory to available therapies. Treatment induced humoral and cellular immunity to NY-ESO-1 in patients with confirmed NY-ESO-1–expressing tumors across various dose levels and adjuvant combinations. No dose-limiting or grade 3 toxicities were reported. Thirteen patients experienced stabilization of disease, with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients had tumor regression (~20% shrinkage in target lesions). Six of eight patients who received immune-checkpoint inhibitors within 3 months after CDX-1401 administration had objective tumor regression. This first-in-human study of a protein vaccine targeting DCs demonstrates its feasibility, safety, and biological activity and provides rationale for combination immunotherapy strategies including immune checkpoint blockade.

Author Summary Lessons Learned Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib. Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations. Background. For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS. Methods. Patients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m2 gemcitabine on days 1 and 8, 75 mg/m2 docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response. Results. The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ≥90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed. Conclusion. GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.

Purpose CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS. Patients and Methods Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active. Results We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive). Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response. Conclusion Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.

Importance More than 90% of well-differentiated or dedifferentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200 mg daily for 14 days every 21 days) resulted in clinical benefit in WD/DDLS but moderate hematologic toxic effects. It is important to understand whether palbociclib at a new dose and schedule—125 mg daily for 21 days every 28 days—results in clinical benefit and manageable toxic effects. Objective To determine the progression-free survival (PFS) at 12 weeks of patients with WD/DDLS treated with palbociclib (PD0332991). Design, Setting, and Participants In this phase 2, nonrandomized, open-label clinical trial conducted at the Memorial Sloan Kettering Cancer Center, 60 patients 18 years and older with advanced WD/DDLS and measurable disease by RECIST 1.1 were enrolled from December 2011 to January 2014 and followed to March 2015. Patients received oral palbociclib at 125 mg daily for 21 days in 28-day cycles. Main Outcomes and Measures Primary end point was PFS. Secondary end points included response rate and toxic effects. Results Overall, 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort. Median (range) age was 61.5 (35-87) years; 31 patients (52%) were male; median (range) Eastern Cooperative Oncology Group score was 0 (0-1). Progression-free survival at 12 weeks was 57.2% (2-sided 95% CI, 42.4%-68.8%), and the median PFS was 17.9 weeks (2-sided 95% CI, 11.9-24.0 weeks). There was 1 complete response. Toxic effects were primarily hematologic and included neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]) but no neutropenic fever. Conclusions and Relevance In patients with advanced WD/DDLS, treatment with palbociclib was associated with a favorable PFS and occasional tumor response. This dose and schedule appears active and may have less toxic effects than 200 mg for 14 days. Trial Registration clinicaltrials.gov Identifier:NCT01209598

11065Background: Desmoid tumors (DT) are rare fibroblastic neoplasms with a variable course. Observation, surgery, radiation and systemic agents are known therapies with variable outcomes. We previously reported on the efficacy of sorafenib (SO). Here we review a larger cohort with long-term follow up (FU). Methods: Patients (pts) with DT treated with SO were retrospectively identified. Baseline/treatment characteristics were analyzed using descriptive statistics. Response rates (RR) were calculated according to RECIST 1.1 and WHO criteria. Kaplan-Meier curves were estimated for survival and variables correlated with treatment outcomes were investigated. Results: We treated 79 pts with progressive or symptomatic DT with SO; median age was 37 years (range 17-81), 67% were female. Primary sites included extremities (n = 22; 28%), abdomen (n = 19; 24%), chest wall (n = 15; 19%), abdominal wall (n = 13; 16%) and other (n = 10; 13%). SO was the first systemic treatment in 49 pts (62%), most frequently at 400mg...

11066Background: UPS, formerly termed malignant fibrous histiocytoma (MFH) are high grade sarcomas where the cell of origin is unkown. Although they represent 15% of sarcomas, there is sparse data ...

Purpose: Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas. Experimental Design: Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion. Results: Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m2 bolus; 50 mg/m2 bolus + 40 mg/m2 infusion) both in combination with doxorubicin (60 mg/m2). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing Cmax with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks. Conclusions: The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified. Clin Cancer Res; 18(9); 2638–47. ©2012 AACR.

Data regarding the role of anthracyclines and taxanes as first-line treatments of metastatic angiosarcoma are limited.Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed.Seventy-five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single-agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression-free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9-6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4-10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS.First-line single-agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS.

Data regarding the management and outcome of patients with metastatic gastrointestinal stromal tumors (GIST) refractory to 1st-line imatinib and 2nd-line sunitinib are limited.Medical records of 223 imatinib-resistant and sunitinib-resistant GIST who were treated in 11 major referral centers were reviewed.The three most frequent drugs used in the 3rd-line setting were: nilotinib n = 67 (29.5%), sorafenib n = 55 (24.5%), and imatinib n = 40 (17.5%). There were 18 patients (8%) who received best supportive care (BSC) only. The median progression-free survival (PFS) and overall survival (OS) on 3rd-line treatment were 3.6 months [95% confidence interval (95% CI), 3.1-4.1] and 9.2 months (95% CI, 7.5-10.9), respectively. Multivariate analysis showed that, in the 3rd-line setting, albumin level and KIT/PDGFRA mutational status were significantly associated with PFS, whereas performance status and albumin level were associated with OS. After adjustment for prognostic factors, nilotinib and sorafenib provided the best PFS and OS. Rechallenge with imatinib was also associated with improved OS in comparison with BSC.In the 3rd-line setting, rechallenge with imatinib provided limited clinical benefit but was superior to BSC. Sorafenib and nilotinib have significant clinical activity in imatinib-resistant and sunitinib-resistant GIST and may represent an alternative for rechallenge with imatinib.

The insulin-like growth factor-1 receptor (IGFR1) is frequently overexpressed in a broad range of tumors. Its signaling has been shown to be involved in tumorigenesis and metastatic potential of multiple cancers.1 Drugs targeting this pathway began to be developed in the late 1990s, including monoclonal antibodies to IGFR1.2 Cixutumumab (IMC-A12; ImClone Systems, Bridgewater, NJ), a fully humanized monoclonal IgG1 antibody, binds to IGFR1 with high affinity, inhibiting its activation.3 Because IGFR1-targeted therapy is relatively new, the potential toxicities are not fully understood. IGF-1 has many physiologic roles that could potentially be compromised by the inhibition of its receptor. One of these roles is to enhance epidermal proliferative potential as well as keratinocyte cell migration.4 Therefore, potential dermatologic adverse effects can be anticipated when IGFR1 function is inhibited. An in-depth review of the literature did not reveal any previous reports that have addressed this issue. In this article, we describe four patients who were enrolled onto clinical trials using cixutumumab and subsequently developed skin and nail abnormalities.

BACKGROUND: In the current study, the authors examined the outcomes of patients with desmoid tumors who received systemic therapy at a single institution to provide a basis for the examination of newer agents. METHODS: Records of patients with desmoid tumors who were treated with chemotherapy at the study institution were reviewed. The activity of nonsteroidal anti-inflammatory drugs was not addressed. Patients without measurable disease and those receiving therapy could not be documented, and those receiving prophylactic therapy were excluded. RESULTS: A total of 68 patients received 157 lines of therapy. At the time of last follow-up, 9 patients had died, 7 of progressive disease. The cohort was 62% female, with a median age of 32.5 years. Approximately 32% of the patients had Gardner syndrome. The median follow-up was 63 months, and patients received a median of 2 lines of therapy. An intra-abdominal primary tumor location was the most common (44%). The greatest Response Evaluation Criteria in Solid Tumors (RECIST) response rate was observed with anthracyclines and hormonal therapy and the lowest response was noted with single-agent dacarbazine/temozolomide or tyrosine kinase inhibitors, principally imatinib. On multivariate analysis, macroscopic nodular morphology and the presence of Gardner syndrome were the only tumor factors found to be associated with a greater time to disease progression. CONCLUSIONS: Compared with other agents, antiestrogens and anthracycline-containing regimens appear to be associated with a higher radiological response rate against desmoid tumors. Systemic therapy can be successful in patients with desmoid tumors, and is a viable option in lieu of morbid or disabling surgery.

Extraskeletal myxoid chondrosarcoma (EMC) is a genetically distinct sarcoma with a propensity for local recurrence and metastasis despite an indolent course. To the authors' knowledge, there are limited data examining chemotherapy outcomes as a guide to therapeutic decisions for unresectable disease.The clinical behavior and treatment responses of 87 patients with EMC who were seen at 2 institutions between 1975 and 2008 were examined.The median age of the patients at the time of diagnosis was 49.5 years, with a male-to-female ratio of 2:1. For patients presenting without metastases, 37% developed local recurrence (median time of 3.3 years) and 26% developed distal recurrence (median time of 3.2 years). Approximately 13% of patients presented with metastases. The 5-year, 10-year, and 15-year overall survival rates were 82%, 65%, and 58%, respectively. Twenty-one patients received 32 evaluable courses of chemotherapy. No significant radiologic or clinical responses were noted. The median time to disease progression while receiving chemotherapy was 5.2 months. The best physician-assessed response to chemotherapy was stable disease for at least 6 months in 25% of patients, stable disease for6 months in 41% of patients, and disease progression in 34% of patients. The estimated progression-free survival rates at 3 months, 4 months, 6 months, and 9 months were 69%, 65%, 40%, and 26%, respectively.This retrospective review highlights the poor response rate to chemotherapy and emphasizes aggressive control of localized disease as the primary approach to management. Although there are biases inherent in retrospective analyses, these data provide a benchmark for time to disease progression for the study of new agents for the treatment of patients with this diagnosis.

Objective We report a single-institution Phase I or II trial of surgical debulking, intraperitoneal chemotherapy, and immunotherapy followed by whole abdominal radiotherapy in patients with malignant peritoneal mesothelioma. Methods Between 1997 and 2000, 27 patients with malignant peritoneal mesothelioma were enrolled: 23 with epithelial subtype and 4 with sarcomatoid or mixed subtype. The treatment regimen consisted of surgical debulking followed by 4 intraperitoneal courses of cisplatin alternating with 4 courses of doxorubicin, 4 doses of intraperitoneal gamma interferon, a second laparotomy with resection of residual disease plus intraoperative intraperitoneal mitomycin and cisplatin heated to 41 degrees C, and finally whole abdominal radiotherapy. Results The median overall survival was 70 months with a 3-year survival of 67% (95% confidence interval, 46%-81%). Fourteen patients have died of their disease with a median time to death of 17 months (range, 0.4-71 months) after consenting to treatment. Seven patients are alive without evidence of disease with a median follow-up of 90 months (range, 71-110 months), and 6 are alive with disease with a median follow-up of 86 months (range, 70-106 months). The regimen was well tolerated. There were no patients with Grade III or IV hematological toxicities, 2 patients with Grade III ototoxicity, and 3 patients with Grade III gastrointestinal toxicity. Conclusion Based on the results of this study, intensive multimodality therapy appears feasible and effective in this group of patients.

We assessed the efficacy of combined temozolomide and thalidomide in patients with unresectable or metastatic leiomyosarcoma in a phase II single-institution trial. Twenty-four patients were enrolled. Temozolomide (150 mg/m2/day for 7 days every other week) was administered with concomitant thalidomide (200 mg/day), and continued until unacceptable toxicity or disease progression. There were no complete responses and two (10%) partial responses. Five patients (24%) had stable disease for at least six months. Fourteen patients (67%) progressed after a median of two-month treatment. The median overall survival (twenty-two assessable patients) was 9.5 months [95% CI 7–28 months]. There were no treatment-related deaths or CTC grade 4 toxicities. Thirteen patients were dose-reduced or discontinued thalidomide due to toxicity. In conclusion, this combination of temozolomide and thalidomide provided disease stabilization in a subset of patients with advanced leiomyosarcoma. We hypothesize that temozolomide is the active agent in this regimen, and should be further studied.

Summary Purpose The purpose of this open-label phase II SWOG study was to evaluate the activity of gemcitabine (Gemzar®; Eli Lilly, Indiana, USA) and cisplatin combination therapy, in patients with unresectable malignant mesothelioma of the pleura. Patients and methods Fifty eligible chemotherapy naive patients with histologically proven malignant mesothelioma of the pleura, and a SWOG performance status 0–2 were enrolled between February 1999 and August 2000. Treatment consisted of gemcitabine 1000 mg/m2 and cisplatin 30 mg/m2 on days 1, 8 and 15 of a 28-day cycle, until progression of disease or two cycles beyond complete response. Results Using SWOG response criteria, one patient had a confirmed complete response and five patients had a confirmed partial response, for a total response rate of 12% (95% CI 5–24%). All the responses were seen in patients with epithelioid or unspecified histology. Stable disease was seen in 25 patients (50%). The median overall survival was 10 months (95% CI 7–15 months), with a median progression-free survival of 6 months. Sixteen patients experienced Grade 4 toxicity. Twelve of these Grade 4 toxicities were hematologic. There were no treatment-related deaths. Conclusions Cisplatin–gemcitabine combination chemotherapy has modest activity with an acceptable toxicity profile, as first line treatment for patients with malignant mesothelioma.

In a randomized phase III trial, pemetrexed plus cisplatin was associated with improved survival compared with cisplatin alone for patients with malignant pleural mesothelioma (MPM). However, there are limited data available on the efficacy of these and other chemotherapy regimens in patients who have received previous systemic chemotherapy. To gather additional efficacy and safety data of pemetrexed/cisplatin and pemetrexed alone in previously treated patients, we examined patients treated on the Eli Lilly and Company expanded access program (EAP).Patients with malignant mesothelioma were enrolled in this trial. Of 1056 patients receiving at least one dose of the study drug, 187 (17.7%) were previously treated patients with MPM. Patients were treated every 21 days with pemetrexed 500 mg/m alone (n = 91) or in combination with cisplatin 75 mg/m (n = 96) for a maximum of six cycles. All patients received folic acid and vitamin B12 supplementation and steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmaco-vigilance database for all patients enrolled in the EAP.Median age of the previously treated pleural mesothelioma subset was 66 years (range, 27-87 years). Based on 153 evaluable patients (a subset of the larger intent-to-treat population of 187), the overall response rate was 32.5% for pemetrexed and cisplatin and 5.5% for pemetrexed alone. The disease control rate (response rate + stable disease) was 68.7% for pemetrexed and cisplatin and 46.6% for pemetrexed alone. Median survival was 7.6 months for pemetrexed plus cisplatin (67% censored) and 4.1 months for pemetrexed alone (55% censored). The most commonly reported serious adverse events in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%).The data from this EAP study suggest that patients with previously treated MPM can benefit from treatment with pemetrexed alone or in combination with cisplatin. The treatment is associated with acceptable toxicity.

10569 Background: Sarcomas are a heterogeneous group of malignancies with diverse genetic abnormalities. Selinexor is a first-in-class, oral, inhibitor of XPO1, (nuclear exportin protein 1) with potent anti-tumor activity in multiple sarcoma cell lines and in murine liposarcoma xenografts. Here we report results from a Phase 1b dose expansion trial of selinexor in sarcoma patients (NCT01896505). Methods: Patients (pts) with advanced, refractory sarcomas with radiographic progression received oral selinexor at 50 mg/m2 twice weekly per 28 day cycle. Pharmacokinetics (PK, n = 12) was assessed in the fasted and fed state. Pharmacodynamic studies were performed on fresh tumor biopsies. Response was evaluated every 2 cycles (RECIST 1.1). Results: 36 pts (14 M / 22 F, ECOG 0/1: 19/17, median age 57.5 years [range 18–86], median lines of previous treatments: 3 [range 1–9]). Disease subtypes include liposarcoma (LPS; N = 12), leiomyosarcoma (LMS; N = 8) and other sarcomas (N = 16). Grade 3 drug related adverse ev...

10574 Background: Non-uterine Leiomyosarcoma (LMS) is an aggressive, malignant tumor of mesenchymal origin whose natural history is poorly defined. We sought to evaluate clinical and treatment outc...

BACKGROUND. TZT-1027, a novel chemotherapeutic agent, is derived from dolastatin 10, and blocks cells during G2/M-phase by interfering with microtubule assembly and stability. TZT-1027 has exhibited potential cytotoxic activity in several human cancer cell lines (in vitro) and also demonstrated antitumor activity in human xenografts (in vivo). In addition, Phase I clinical investigations suggested activity in STS (soft-tissue sarcoma). METHODS. Eligible patients were those who had histologic evidence of locally advanced or metastatic STS and who had received 1 prior treatment regimen with an anthracycline-based chemotherapy for metastatic disease. Subjects received intravenous infusions of TZT-1027 over 1 hour on Day 1 and Day 8 of each 21-day treatment course. Efficacy was evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS. Twenty-nine patients were enrolled and 28 patients received at least 1 course of study drug and were eligible for efficacy and safety evaluation. The median age of the patients was 48 years (range, 23–73 years) and the median baseline Eastern Cooperative Oncology Group (ECOG) performance status was 1 (range, 0–2). A total of 67 courses (range, 1–9 courses; median, 2 courses) of TZT-1027 were administered. No patient in the study demonstrated an objective response to treatment. Of 6 patients (21.4%) who experienced disease stabilization, 1 continued to have stable disease for 9.3 months. The median time to tumor progression was 44 days (95% confidence interval [95% CI], 43.0–54.0) and the median survival was 178 days (95% CI, 134.0–317.0). The most commonly reported toxicities were neutropenia, fatigue, and constipation. CONCLUSIONS. TZT-1027 was found to be safe and well tolerated, and the hematologic toxicities observed were consistent with preclinical toxicology and Phase I study findings. No confirmed responses were seen in the current study. Cancer 2006. © 2006 American Cancer Society.

Introduction. The role of vinorelbine in specific soft tissue sarcoma subtypes is unclear. We present retrospective single institution experience with single-agent vinorelbine in subjects with metastatic soft tissue malignancies.Methods. Fifty-eight patients were treated with single agent intravenous vinorelbine between April 1997 and December 2004. Doxorubicin had been administered previously to 53 subjects (91%), and the median number of lines of previous chemotherapy was 3 (range 0–7).Results. Patients received a median 6 doses of vinorelbine (range 1–65). The overall response rate was 6%(3 patients: 1 angiosarcoma, 1 epithelioid sarcoma, and 1 embryonal rhabdomyosarcoma). Fourteen patients (26%) experienced a best result of stable disease. Median time to progression was 1.8 months (95%confidence intervals 1.5–2.1 months, Kaplan-Meier estimate). Eight patients experienced grade 3 or 4 toxicity, most commonly febrile neutropenia.Conclusion. Vinorelbine demonstrates limited activity in a heavily pretreated group of soft-tissue sarcoma patients. Prospective investigation may be considered for selected sarcoma subtypes.

Sarcomas are rare but aggressive malignant tumors associated with high mortality, for which the efficacy of standard therapies remains limited. In order to develop immunotherapeutic approaches for the treatment of sarcoma, we studied the relevance of cancer/testis antigens (CTAs), a group of antigens whose expression is developmentally regulated and that is specifically found in some tumor types, as sarcoma vaccine targets. CTA expression was assessed by PCR and/or immunohistochemistry (IHC) in sarcoma tumor samples that included different histological subtypes and sarcoma cell lines. Expression of HLA class I was assessed by IHC in tumor samples and by FACS analysis in cell lines. More than 70% of the tumor samples expressed at least one CTA. The majority of tumors and cell lines expressed normal levels of HLA class I. HLA class I expression in cell lines was enhanced upon treatment with IFN-gamma. CTA expression was enhanced or induced by treatment with the demethylating agent 5-aza-2'-deoxycytidine, resulting in recognition by specific CTLs. Interestingly, a spontaneous humoral and CD8+ T cellular response to the CTA NY-ESO-1 was detected in a synovial sarcoma patient. Together, these findings strongly support the implementation of CTA-based immunotherapy of sarcoma as a means to improve the efficacy of the standard therapy.

The purpose of this study was to validate the content and structure of the Multidimensional Affect and Pain Survey (MAPS) by means of factor analysis. The 101-MAPS is based on a dendrogram obtained by cluster analysis and contains 30 clusters subsumed within three superclusters. If the MAPS is a valid questionnaire for the quantification of emotion and pain in patients, then factor analysis of patients' intensity ratings should produce factors which correspond to the cluster structure of the dendrogram. To confirm the structure of the dendrogram and hence, MAPS, factor analysis was applied to the responses by 100 outpatients diagnosed with early stage cancer. Principal components analysis of responses to the MAPS yielded six factors. In accordance with the hypothesis, 13 of the 17 clusters within the MAPS somatosensory pain supercluster loaded on three sensory factors: factor 1, severe sensory pain; factor 3, moderate sensory pain; and factor 6, numb/cold. Five of the eight clusters within the emotional pain supercluster loaded on factor 2, negative emotions. Four of the five clusters in the well-being supercluster loaded on factor 4, good health. Factor 5, manageable illness was loaded on by clusters from the well-being supercluster and the somatosensory pain supercluster. The homogeneity of the six factors found demonstrate the validity of the MAPS and the cluster structure of the dendrogram. MAPS proved sensitive to sex differences; women endorsed the negative emotions factor more strongly than did men. The MAPS factors were much more homogeneous than those reported in the literature for the McGill Pain Questionnaire.

BACKGROUND The objective of this study was to assess the efficacy and toxicity of the imidazotetrazine derivative temozolomide for patients with unresectable or metastatic soft tissue sarcoma. METHODS Twenty-five of 26 patients were eligible and assessable for toxicity and response. Temozolomide was administered twice daily on a 12-hour schedule for 5 days as an oral bolus dose of 200 mg/m2 followed by 9 doses of 90 mg/m2 every 4 weeks. RESULTS There were 2 partial responses, 2 mixed responses, and 3 patients with stable disease that lasted > 6 months, for an overall objective response rate of 8%. At a median follow-up of 13.2 months, the median progression-free survival and the median overall survival were 2.0 months (95% confidence interval [95% CI], 1.7–2.3) and 13.2 months (95% CI, 4.7–31.1), respectively. All responding patients had leiomyosarcoma of uterine or nonuterine origin; and, in a subset analysis of these patients, the objective response rate was 18% (2 of 11 patients), with disease stabilization occurring in 3 of 11 patients (27%). For this subgroup, at a median follow-up of 24.4 months, the median progression-free survival and the median overall survival were 3.9 months (95% CI, 1.9–21.9) and 30.8 months (lower-bound 95% CI, 7.8), respectively. There were no treatment-related deaths or National Cancer Institute Grade 4 toxicities. Grade 3 toxicities included nausea, anemia, fatigue, elevated alkaline phosphatase levels and nonneutropenic fever (1 patient each). CONCLUSIONS Temozolomide at the dose schedule employed in the current study was tolerated well and had modest activity against previously treated unresectable or metastatic leiomyosarcoma of both uterine and nonuterine origin. Cancer 2003. © 2003 American Cancer Society.

The efficacy of current standard therapies for the treatment of sarcoma remains limited. With the aim of identifying target antigens relevant to the development of vaccine-based immunotherapy of sarcoma, we have addressed the relevance of tumor-specific antigens encoded by genes belonging to the SSX family as vaccine targets in sarcoma tumors. Expression of SSX-1 to -5 was analyzed in a collection of sarcoma tumors of diverse histological subtypes and in sarcoma cell lines. We found expression of at least one SSX-encoded antigen in 42% of sarcoma tumors, including 5 of 7 different histological subtypes, and in 50% of sarcoma cell lines. SSX-1 was the most frequently expressed family member, followed by SSX-4, -2 and -5. Expression of SSX-3 was detected in only one sample. Importantly, most SSX positive samples co-expressed more than one family member. In addition, assessment of CD8+ T cell recognition of HLA-A2+ SSX-2+ sarcoma cells showed that the latter were efficiently recognized and lysed by SSX-2-specific CTLs. The results of this study indicate that SSX antigens are relevant targets for the development of vaccine-based immunotherapy of sarcoma and encourage the start of vaccination trials using SSX-derived immunogens in sarcoma patients.

10521 Background: Few effective treatments (tx) exist for patients (pts) with tyrosine kinase inhibitor (TKI)-resistant gastrointestinal stromal tumors (GIST) and other advanced soft tissue sarcoma...

10522 Background: Programmed death-1 (PD-1) is a member of the CD28 family of T-cell costimulatory receptors that attenuates immune responses by negatively regulating T-cell proliferation and function. The prognostic and predictive implications of programmed death-ligand 1 (PD-L1) has been described in multiple malignancies but are unknown in sarcoma. We previously demonstrated PD-L1 expression by western blot and flow cytometry in 65% of sarcoma cell lines. We now examined PD-L1 expression by IHC in sarcoma specimens and tumor-associated immune cells and correlated expression with clinical parameters and outcomes. Methods: 50 sarcoma patients treated at Memorial Sloan Kettering Cancer Center who were consented to our IRB approved tissue procurement protocol were selected. Correlative clinical information was collected.Using the DAKO PD-L1 IHC assay and archival formalin-fixed paraffin embedded tissue specimens; PD-L1 expression was examined. Positive was defined as >1% of tumor cells (minimum of 100 eval...

10582 Background: DSRCT is a rare, aggressive, and poorly understood neoplasm characterized by the EWS-WT1 translocation. Prognosis is poor despite upfront multimodality therapy with surgery, radia...

10558 Background: Our group previously reported that PDGFRA is the most highly overexpressed kinase gene in synovial sarcoma. Our preclinical studies also demonstrated synergistic anti-tumor activity by inhibiting both PDGFRA and mTOR signaling with imatinib and rapamycin respectively in PDGFRA + synovial sarcoma cell lines. Based on these data, a phase Ib/II study to evaluate the toxicity and efficacy of imatinib and everolimus was undertaken. Methods: The primary endpoint of the phase 1b portion of the study was to determine the maximum tolerated dose (MTD) of everolimus administered with imatinib. Starting dose of everolimus and imatinib was 5 mg/day and 400 mg/day respectively. Response rate (RR) by RECIST was the primary end-point of the Phase II study. The phase II study used a Simon two stage design. 9 patients (pts) were to be accrued initially. If there were no responses, further accrual would be stopped and treatment declared ineffective. If there was at least 1 response, an additional 15 pts would be accrued for a total of 24. Key eligibility: metastatic disease, any number of priors. Pre and post treatment tumor biopsies were mandated. Results: 12 pts were treated.5 M and 7 F, median age 44 (range: 22-71), median priors 4 (range: 0 - 6). Two DLTs were observed at dose level 2 (10 mg everolimus /400 mg imatinib) with grade 3 transaminases and hypophosphatemia. Everolimus 5 mg/ imatinib 400 mg was the MTD in the phase II study. 10 pts evaluable for response, included 4 pts treated at the MTD in the Phase 1b study. There were no RECIST responses. Stable disease was observed in 3 pts (7, 7, 19 mos.). Western blot and IHC analysis of matched pair tumor biopsies indicate inhibition of p-AKT, p-S6 and decreases in Ki 67. Conclusions: Imatinib and everolimus failed to achieve its primary response endpoint. However, prolonged stable disease in 3 pts in association with inhibition of PDGFRA and mTOR suggest clinical benefit and biological effect for this drug combination. Clinical trial information: CTEP 8603.

10512 Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ≥ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (≥1+). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting > 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.

10580 Background: Angiosarcoma (AS) is a rare, malignant endothelial cell tumor of vascular origin with a five year overall survival (OS) of approximately 35%. It is a heterogenous disease whose natural history is poorly defined. We sought to identify clinical and treatment outcomes to better define this disease. Methods: In a retrospective study using an institutional sarcoma database, we identified all patients(pts) with AS treated at Memorial Sloan-Kettering Cancer Center between 1992-2011 and collected their correlative clinical information.Kaplan-Meier method and Cox’s proportional-hazard models were used to determine OS and prognostic factors. Hazard ratios (HR) are listed with their 95%confidence intervals (CI). Results: We identified 324 pts, median age was 63 (range 15-94), 127(39%) were men. At presentation, 188 (58%), 19 (6%) and 117(36%) had localized disease (L), local recurrences (LR) or distant metastases (M), respectively. L sites included: RT breast 43 (23%,) head&neck 33 (18%,) scalp 30 (16%,) breast 26 (14%,) extremity 23 (12%,) abdomen/pelvis 14 (7%,) thorax 10 (5%) and trunk 9 (5%). The median OS is 3.3 years (2.44-4.33) for pts w L disease and 0.89 years (0.74-1.11) for pts with M disease. Among pts that presented with L disease, 29% had a LR and the median local relapse free survival (RFS) time was not reached (8.71-NA); 31% had distant recurrences with a median distant RFS of 12.8 yrs (4.13-NA.) Among L disease patients, older age (HR 1.04, 1.03-1.06, p

10019 Background: Angiosarcomas (ASs) are rare, aggressive vascular malignancies of endothelial cell differentiation which arise de novo or secondary to radiation therapy (RAS.) A subset of patients(pts) with AS harbor mutations in KDR (VEGFR-2) or overexpression of MYC and/or FLT4(VEGFR-3). MYC & FLT4 gene amplifications occur almost exclusively in RAS. These alterations provide a rationale for investigating agents that target angiogenesis in RAS. In a phase II trial of sorafenib, AS pts had a partial response (PR) of 14%; targeting the appropriate pt population may be essential. We hypothesize that co-amplification of MYC & FLT4 may be predictive of response to sorafenib. Methods: Using our institutional sarcoma database & data query system, we identified AS patients treated with sorafenib at Memorial Sloan-Kettering Cancer Center between 1992-2011. Molecular analysis performed on available tissue. With IRB approval, clinical information was collected. Results: We identified 10 women with RAS that received sorafenib. Average age 68 (range 51-84.) 7 pts had distant metastatic disease. Median lines of systemic therapy prior to sorafenib: 2 (range 1-4.) Sorafenib was first line in 60% of pts, administered at 400mg daily and adjusted for toxicity. Best responses included: complete response (CR) 2/9(22%), PR 1/9(11%), stable disease (SD) 5/9(56%) range 5-23m, progressive disease 1/9(11%) for a clinical benefit rate of (CR+PR+SD) 89%. Responses were seen in patients with lung metastases (n=2) and locally advanced disease (n=1) and were durable for 17, 42 and 26 months. Median duration on therapy was 15 months (range 0-42 months.) 7 pts underwent molecular analysis: co-amplification of MYC & FLT4 3 pts (30%); MYC amplification 4 pts (40%); KDR mutation 0 patients. Of the 3 responders, MYC & FLT4 co-amplification were observed in 2 patients and not evaluated in one. Conclusions: Sorafenib is active against RAS of the breast. In this small series, complete and partial responses were seen in patients with co-amplification of MYC & FLT4. This observation requires further study. Performing molecular studies on all AS pts will help define the pathophysiology of this deadly disease to guide rationale clinical trials.

10002 Background: CDK4 is amplified in approximately 90% of well-differentiated/de-differentiated liposarcomas (WD/DDLS). The selective CDK4/CDK6 inhibitor PD0332991 (PD) inhibits growth and induces senescence in liposarcoma cell lines and xenografts. In a phase I trial of PD, several patients with progressive WD/DDLS had prolonged stable disease for several years. To determine the safety and efficacy of PD, a phase II study was performed. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age≥18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥1+). Pts received oral PD 200mg daily for 14 consecutive days in 21-day cycles. The primary endpoint was progression-free survival (PFS) at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD would be considered to have activity in WD/DDLS. Results: Of 44 patients screened (42/44 CDK4 amplified; 41/44 RB+), 29 were enrolled and 27 were evaluable for the primary endpoint. Median age was 65 (range 37-83); 52% were male; ECOG scores were 0 (69%) or 1 (31%), and the median number of prior regimens was 1 (range 1-5). PFS at 12 weeks was 70% (19/27 patients; 90% CI 56-100%), and thus the study significantly exceeded its primary endpoint. At the data cutoff, the median PFS was 18 weeks. Seven patients remain on study with stable disease at 18-48 weeks of followup. Grade 3 and 4 events included anemia (grade 3, 14%), thrombocytopenia (grade 3, 17%; grade 4, 14%), neutropenia (grade 3, 41%; grade 4, 7%) and febrile neutropenia (3%). Dose reductions were required in 24% of patients. Conclusions: Among patients with WD/DDLS with CDK4 amplification and RB expression who had actively progressing disease despite prior systemic therapy, treatment with the CDK4 inhibitor PD0332991 was associated with improved PFS. A randomized phase 3 trial is planned.

10025 Background: Sorafenib has a low single agent RR in sarcoma. Other angiogenesis inhibitors are more effective when combined with standard chemotherapy. Sorafenib has been safely combined with dacarbazine for treatment of melanoma. As PRs, MRs and prolonged SD were seen in LMS, SS and MPNST in our single agent S study, we chose to investigate S+D in those histologies. Methods: Patients with LMS, SS or MPNST with up to 2 priors, and adequate hepatic, renal and marrow function receive S at 400 mg BID and D at 1000mg/m2 every 3 weeks. Pts are restaged every 2 cycles. The primary objective of this trial is to determine Clinical Benefit Response rate (CBR=CR+PR + SD x18 weeks) of S+D in these subtypes. A Simon two stage design to distinguish between a CBR rate of 20% and 40% required 4 CBRs out of the first 17 pts to expand to a second cohort, and 11/37 (29.7%) CBRs to be considered positive. Results: From 2/09-12/10, 31 pts have been enrolled: 17 F, 14 M; median age 55, range 27-80; ECOG PS 0 16, 1 14; 20...

10079 Background: Data regarding the management of patients with metastatic EHE are almost nonexistent. Methods: From 1990 to 2010, 78 adult patients (pts) with a confirmed diagnosis of EHE were re...

10013 Background: DT/DFs are clonal connective tissue malignancies that do not metastasize, but have a significant risk of local recurrence, and are often associated with morbidity and occasionally mortality. Antiestrogens and cytotoxic agents have activity against desmoids, but many patients (pts) fail to respond to such therapy. Imatinib has activity against DT/DF, but response rates are also low. A response of a patient to sorafenib on an expanded access program led us to review our experience with sorafenib for pts with DT/DF. Methods: After IRB approval, we collected and reviewed files for 13 patients with DT/DF treated with sorafenib. Results: We identified 13 pts who received sorafenib for DT/DF. Patient characteristics included: M/F: 6/7; extremity primary site in 4 (31%), abdomen/pelvis in 6 (46%), other in 3 (23%); recurrent disease in 8 (61%); 2 with FAP (15%); 3 with post-surgical DT/DF (23%); multifocal in 6 (46%). Pts had received a median of 2 lines of systemic therapy (range 0-5). Sorafeni...

10637 Background: Several sarcoma subtypes are characterized by well-defined genetic events such as chromosomal translocations or gene amplification. In translocation-associated sarcomas, the prese...