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

e23568Background: Immune checkpoint inhibitors revive pre-existing immune responses that are suppressed in cancer. To restore tumor surveillance that is lost in cancer patients, a tumoricidal agent...

TPS11589Background: PEComas are rare mesenchymal tumors with a female predominance, composed of epithelioid cells that show a focal association with blood vessel walls and usually express both mela...

2537Background: Here we present a study combining BAY1217389 (BAY), a potent MPS-1 kinase inhibitor with a backbone chemotherapy paclitaxel. Since we expected overlapping toxicities we sought to im...

40 Background: To restore innate tumor surveillance that is lost in cancer patients, a tumoricidal agent may have synergistic activity with an immune checkpoint inhibitor. Herein, we report on a retrospective analysis of our clinical experience using trabectedin, an alkylating agent, and nivolumab, a PD-1 inhibitor in advanced soft tissue sarcoma. Methods: Twenty previously treated STS patients received trabectedin (1.5 mg/m2 continuous intravenous infusion, CIV, for 24 hours) every 3 weeks, and nivolumab (3 mg/kg IV over 30 minutes) every 2 weeks. Safety/toxicity was analyzed using the NIH/NCI CTCAE v.4.03. Tumor responses were assessed by RECIST v1.1 and immune-related response criteria (irRECIST). Results: Histologic subtypes in 20 patients include undifferentiated pleomorphic sarcoma (UPS; n = 7), leiomyosarcoma (n = 5), synovial sarcoma (n = 2), myxoid liposarcoma (n = 4) and chondrosarcoma (n = 2). All patients had metastatic disease and a median of 4 lines of prior chemotherapy. Safety analysis (n = 20): Grade 3 treatment emergent adverse events include anemia (n = 2), fatigue (n = 1), decreased platelet count (n = 1), decreased granulocyte count (n = 1) and increased creatine kinase (n = 1). Efficacy analysis (n = 17): Seventeen patients were followed for at least 6 months and their results are reported here. There were 4 partial responses (UPS = 1, myxoid liposarcoma = 1, chondrosarcoma = 1, leiomyosarcoma = 1), 7 stable disease, and 6 progressive disease, with best overall response rate of 23.5%, median progression free survival (PFS) of > 11.6 months (range: 2.3- > 16.9 months), median overall survival (OS) of > 14.2 months (4.5- > 24.0 months), 6 month PFS rate of 64.7%, and 6 month OS rate of 94.1%. In a Phase 3 study, the median PFS was 4.2 months using trabectedin alone (Demetri et al., 2015). Conclusions: Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immuno-therapy approach has synergistic activity.

11021Background: Giant cell tumours of bone (GCTB’s) are RANK-ligand (RANK-L) positive, aggressive and progressive osteolytic tumors. Denosumab, a RANK-L inhibitor, was FDA-approved for adults and ...

11051 Background: Aldoxorubicin (A) has demonstrated superior anti-tumor efficacy and lack of cumulative cardiac toxicity in multiple studies. A is doxorubicin (D) with a linker which rapidly binds in vivo to albumin after iv. We studied the combination of A administered on Day 1 with continuous infusion (CI) of ifosfamide/Mesna (I-M) days 1-14, as first line therapy or second line therapy in patients with soft tissue sarcomas (STS) to evaluate efficacy and toxicity. Methods: 27 patients have entered the study at 250 mg/m2 ( 185 mg/m2 D equiv) administered on Day 1. I-M (1 g/m2 of each per day) was given up to 14 days as a CI via an out-patient portable pump. Chemotherapy cycles were repeated at 28 day interval. I-M was limited to a maximum of 6 cycles to avoid cumulative marrow toxicity, but A was continued per investigator decision in responding or SD patients for clinical benefit. Subjects were followed for tumor response (RECIST 1.1) by CT scans and echocardiogram/ECG for cardiac toxicity every 8 weeks along with standard labs. Enrollment continues up to 50 patients. Results: Demographics: Leiomyosarc. = 20%, liposarc. = 20%, synovial sarc. = 20%, rhabdosarc. = 8%, others = 32%. Caucasian, 11% Asian, 4% Black; 67% no prior tx, 26% 1 prior tx, 7% > 1 prior tx; Median cum. A = 1000 mg/m2 (740 mg/m2 D eq.; 185-4070 mg/m2 D eq.); I = 6.9 g/m2 (2.1-12.6 g/m2). Best response: 42% PR, 58% SD. Median PFS not reached. 10 subjects with either PR or SD had surgery to remove accesible tumors. Range of tumor necrosis = 70 to > 95%. Grade 3/4 AEs: neutropenia = 78%, febrile neutropenia = 9%, thrombocytopenia = 22%, anemia = 65%, nausea = 4%. Related SAEs = 4 (febrile neutropenia (2), pyrexia, stomatitis). No tx related deaths. No clinically significant cardiac AEs, no decrease in LVEF > 20% Conclusions: A can be administered for prolonged periods and safely with CI ifosfamide/mesna and achieves high ORR and SD with substantial tumor necrosis. Clinical trial information: NCT02235701.

11078 Background: TGCTis a proliferative, neoplastic joint disease that presents as single nodule (local) or multiple nodules (diffuse D-TGCT). Localized overexpression of colony stimulating factor 1 (CSF1) leads to recruitment of cells expressing the CSF1 receptor (CSF1R), formation of a tumor and inflammation of joints and tendons. Cabira is a monoclonal antibody that inhibits the interaction of the CSF1 and IL-34 ligands with their shared receptor CSF1R. Methods: This Ph 1/2 study is evaluating the safety and efficacy of cabira monotherapy administered IV Q 2wk for 6 mo in patients (pts) with D-TGCT. Eligible pts have inoperable D-TGCT or tumor for which resection would cause unacceptable morbidity. Response is evaluated by MRI, pt reported outcomes, and Ogilvie-Harris (O-H) score (which combines pain, synovitis, range of motion and functional capacity on a scale of 0-12). Results: As of 15 Dec 2016, 22 pts received ≥ 1 dose of cabira at 1, 2 or 4mg/kg. Dose-related exposure increase and significant reduction in target peripheral monocytes were observed. No dose limiting toxicity was identified. 4 mg/kg was chosen for Ph2 based on efficacy, tolerability, and PK. AEs ≥ Gr 2 ( > 10%) were CK elevation 46%, rash and other skin disorders 36%, fatigue 23%, and periorbital/peripheral/face edema 18% each. Gr 3 AEs in ≥ 2 pt were CK elevation (n = 8) and periorbital edema (n = 2). Four drug-related SAEs were reported in 3 pts; hypertension, fever, CRP elevation, and myocarditis. AEs of CK elevation were asymptomatic, improved to < 2X ULN after protocol mandated drug discontinuation and are a known on-target effect of CSF1R inhibition. An amendment was made during Phase 2 to allow dosing with higher CK levels Activity at 4 mg/kg was: 1PR and 1 CK discontinuation in 3 pts in Ph1; 4 PRs in 7 evaluable pts with 6 additional ongoing in Ph2. Positive functional status improvements by O-H score were noted in objective responders (from 2 to 7). Conclusions: The initial demonstration of objective and functional activity supports further development of cabiralizumab in pts with D-TGCT. Updated data from the ongoing Ph2 will be presented. NCT02471716 . Clinical trial information: NCT02471716.

11052Background: Trabectedin (T) is an anti-tumor agent used in the treatment of advanced soft-tissue sarcomas (STS). It interferes with DNA replication, causing double strand breaks and apoptosis,...

11016Background: P, a VEGFR TKI, is approved for advanced STS based on median PFS (mPFS) in the absence of CR. Endoglin is a receptor expressed on tumor vessels that is overexpressed in certain STS...

e22547Background: Ifosfamide (I)+ doxorubicin (D) is considered the most active treatment regimen for soft tissue sarcomas (STS). I is given as a 4-5 day infusion with D administered on Day 1 of ea...

2523Background: Aldoxorubicin (A) is a novel prodrug of doxorubicin (D) that binds covalently to albumin, accumulates in tumors and releases D under acidic conditions. It has demonstrated significant efficacy against soft tissue sarcomas in a phase 2b study versus D. Gemcitabine (G), when combined with various chemotherapies (albumin/paclitaxel nanoparticles, liposomal D) has demonstrated efficacy in patients with pancreatic, ovarian and lung cancers. It was hypothesized that A+G might possess synergistic activity against solid tumors. This study was designed to identifiy the major toxicities of this combination and establish its MTD. Methods: Adults who had relapsed or not responded to prior chemotherapies were eligible. Initial cohorts were (i) A 170 mg/m2+ G 900 mg/m2 ); (ii) A 250 mg/m2 + G 900 mg/m2; and (iii) A 200 mg/m2 + G 750 mg/m2. A was administered on Day 1 and G on Days 1 and 8 of each 21 day cycle. Safety was monitored continuously, cardiac function was assessed every 2 months by echocardiog...

10573 Background: Gemcitabine and docetaxel chemotherapy protocols have proven efficacy in the treatment of metastatic soft tissue sarcomas. Doxorubicin is also a commonly used treatment both as a ...

10514 Background: The VEGFR inhibitor pazopanib is approved for the treatment of advanced STS. Resistance to pazopanib is a challenge in the treatment of STS, and endoglin (CD105) activation may be an important resistance mechanism. Endoglin is an angiogenic receptor expressed on proliferating tumor vessels, which is upregulated following VEGF inhibition and expressed on certain STS subtypes, including angiosarcoma. A phase Ib study of TRC105, an anti-endoglin antibody, in combination with pazopanib was performed in patients (pts) with advanced STS. Methods: Heavily-pretreated STS pts with leiomyosarcoma (11); angiosarcoma (2); synovial sarcoma (2); epithelioid sarcoma (1); myxofibrosarcoma (1); epithelioid hemangioendothelioma (1); and unclassifiable high grade sarcoma (2), ECOG PS 0-1, were treated with infusional TRC105 weekly in two cohorts (8mg/kg and 10mg/kg). TRC105 was initiated following a 2 to 4 week lead-in period of pazopanib starting at 800 mg PO daily. Results: Twenty pts (median age = 57; M...

10528 Background: GCTB are aggressive osteolytic tumors, which are characterized by local bone destruction and soft tissue invasion. There have been limited non-surgical treatments, including radiation therapy. However, an unacceptable rate of post radiation sarcomas has been well established. Such tumors have osteoclast like giant cells/stromal cells that express surface RANK ligand. Denosumab is an FDA approved drug used in the treatment of unresectable GCTB or GCTB with severe morbidity related surgery. It is a monoclonal antibody that targets the RANK ligand characteristic to GCTB. We report our 8-year experience in the treatment of complex GCTB using denosumab. Methods: Review of 43 skeletally mature patients (N = 43) who were treated with subcutaneous (SC) denosumab for the treatment of GCTB, in whom surgery was not feasible without severe morbidity. Denosomab was dosed at 120 mg on days 1, 8, 15, 29, and every 4 weeks thereafter. CT, PET/CT, or MRI was used to determine radiographic disease burden,...

10546 Background: Aldoxorubicin (6-maleimidocaproic acid hydrazide) is a novel prodrug of doxorubicin that binds to the thiol group of cysteine-34 amino acid in circulating albumin. The circulating...

58 Background: GISTs are characterized by KIT/PDGFRA mutations. A range of multi-targeted tyrosine kinase inhibitors (TKIs) are available for treatment, however, resistance mechanisms inevitably emerge. Recent data (Boichuk, et al 2014) suggests the potential efficacy of various cytotoxic therapies that were identified as being able to effectively kill TKI-responsive and -resistant GIST cells. We sought to investigate the theranostic markers associated with non-TKI therapy options for their potential role in treatment of GIST. Methods: 147 GIST cases were evaluated. A multiplatform approach of biomarker testing was used and included a combination of sequencing (NGS, Sanger), protein expression (IHC) and gene amplification (ISH). Results: Multidrug resistance phenotype was found in 52-68% (PGP, MRP1). Tubulin-binding agents (taxanes, vinca alkaloids) may be of potential use due to the high frequency of low TUBB3 expression (72% or 39/54). Anthracyclines and topoisomerase inhibitors may be of potential benefit in 1/3 of patients based on expression of TOPO2A (32% or 32/99) and TOPO1 (34% or 37/110). Cytotoxic agents used in non-GIST solid tumors, may also be considered, based on high frequency of low expressin of MGMT (47% or 57/122), TS (70% or 76/109) and RRM1 (79% or 88/111). PTEN was intact (positive expression) in the majority of GIST (87%). Nine patients were examined for PD1/PDL1: 56% exhibited positive tumor infiltrating lymphocytes and 33% exhibited PDL1 tumor expression. Only one amplification event was observed: cMET (0/53), HER2 (0/69), EGFR (0/16), PIK3CA (0/1) and TOP2A (1/11). Mutational screening using a hot spot cancer panel (and Sanger sequencing for some genes) resulted in the detection of variants in only 10 genes, excluding KIT (97/132) and PDGFRA (5/55). Variants were detected in the following genes, in decreasing order of frequency: RB1, APC and JAK3 (2/55; 2/55; 2/57), PIK3CA (2/69) and ABL1, cMET, EGFR, KDR, VHL and BRAF (1/55, 1/57, 1/57, 1/57, 1/52, 1/78). Conclusions: A multi-platform approach of theranostic biomarkers identified therapies beyond TKIs for GIST. Various cytotoxics and non-KIT/PDGFRA targeted therapies were identified based on protein expression or gene variations.

11113 Background: AV-203 is an IgG1k humanized monoclonal antibody with high affinity and specificity for the anti-v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3) receptor. Based ...

10596 Background: Ifosfamide is commonly used to treat bone and soft tissue sarcomas (STS) and its efficacy appears to increase with doses >9g/m2/cycle. Due to the toxicity associated with bolus do...

10502 Background: Doxorubicin (D) is the only approved first line therapy for most advanced soft tissue sarcomas (STS). Aldoxorubicin (A) consists of doxorubicin attached to an acid-sensitive linke...

2550 Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv + 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 mg/m2 aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) + doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.

2573 Background: IMGN853 is an antibody-drug conjugate (ADC) comprising a folate receptor 1 (FOLR1)-binding antibody and the potent maytansinoid, DM4. FOLR1 is over-expressed on many solid tumors, particularly EOC, endometrial cancer, non-small cell lung cancer (NSCLC), and clear-cell renal cell cancer. Methods: The primary study objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy. In dose escalation, patients with any type of FOLR1-expressing, refractory solid tumor may be enrolled. Once the MTD is defined, 3 expansion cohorts will evaluate patients with (1) primary platinum refractory or resistant EOC; (2) relapsed/refractory EOC, amenable to biopsy, and (3) relapsed/refractory NSCLC. Cohorts 2 and 3 will have IMGN853 PD assessment by pre-and post-dose tumor biopsy and by FLT-PET imaging, respectively. IMGN853 is given intravenously (IV) on Day 1 of each 21-day cycle. During dose escalation, an accelerated titration design was used. Responses are assessed using RECIST and GCIG criteria (as appropriate). Results: Eleven patients have been enrolled across 6 dose levels ranging from 0.15 to 5.0 mg/kg: 7 patients with EOC and 4 patients with endometrial cancer. No study drug-related serious adverse events (SAEs) or dose-limiting toxicity (DLT) have been reported. Among these 11 patients, 3 patients reported adverse events (AEs) considered study drug related; these were mild or moderate. At the 3.3 mg/kg dose level, one patient with serous EOC had an 82% reduction in CA125 (confirmation pending). The other 2 patients at this dose level, one with EOC and one with endometrial cancer, have stable disease. Drug exposure has been measured in 8 patients and has been found to generally increase linearly, with a half life at 3.3 mg/kg (3 patients) of approximately 4 days. Conclusions: IMGN853 is well tolerated at doses up to 3.3 mg/kg. Safety evaluation continues at 5 mg/kg and dose escalation is ongoing. Clinical trial information: NCT01609556.

2609 Background: Liposomal (LIPO) docetaxel (DOCE) formulations may reduce hypersensitivity reactions, eliminate premedication requirements, have a broader therapeutic index, and enhance systemic DOCE exposure. ATI-1123 is a novel LIPO DOCE formulation utilizing human serum albumin that facilitates LIPO tumor targeting. We studied safety, tolerability, pharmacokinetics (PK) and tumor response of ATI-1123 in patients (pts) with advanced solid tumors. Methods: Pts enrolled had progressive disease after standard therapy, measurable disease (RECIST), ECOG ≤ 2, survival ≥ 3 mo. Dosing (1 hr infusion) began at 15 mg/m2 using an accelerated titration design, followed by a modified Fibonacci schema to MTD. Dosing was continued until pts had progressive disease or unacceptable toxicities. Plasma was analyzed for encapsulated / non-encapsulated DOCE using a validated assay. PK was determined by model independent methods. Results: To date, 19 pts were enrolled (median age 62 yr; range 40-80 yr; 58% male; 5 (26%) NSC...

9505 Background: AP23573 is an mTOR inhibitor that has shown anti-tumor activity in phase 1 clinical trials, particularly in patients with advanced sarcomas. Given this observation, this phase 2 trial was undertaken to assess further the efficacy and safety of AP23573 across various sarcoma subtypes. Methods: Advanced sarcoma pts, with no restrictions on prior therapies, were enrolled into 4 cohorts based on histologic subtype, in a phase 2 trial with Simon’s 2-stage design. AP23573 (12.5 mg, i.v.) is administered for 5 days every 2 wks. Efficacy is assessed using RECIST guidelines, with clinical benefit response (CBR) defined as complete or partial response (PR) or stable disease (SD) for at least 16 wks duration. For each cohort, treatment was defined as successful if the proportion of patients with CBR was ≥ 25%. Studies of potential predictive markers of response include 18FDG-PET imaging, analysis of mTOR pathway proteins in tumoral tissue, and measurement of plasma cytokines and angiogenic factors. Results: In total, 216 pts were enrolled as all cohorts met criteria to enter Stage 2 of the trial. Of these pts, 213 were treated (106 M/107 F) (age 17–79 yrs, median 50 yrs). Most frequent related adverse events included mucositis, rash, hyperlipidemia, fatigue, and thrombocytopenia. Preliminary response data for 193 evaluable pts are available: overall 54 (28%) had CBRs, including 5 PRs (3 pts with osteo, 1 with spindle cell of bone, and 1 with MFH). Twenty of 76 pts (26%) imaged with PET had rapid induction of partial metabolic responses following 3 to 5 days of study treatment. Conclusions: Initial assessments from this trial show that single-agent AP23573 is well tolerated and has efficacy in pts with advanced sarcomas that warrants evaluation in phase 3. Analysis of the potential utility of FDG-PET and a broad set of candidate biomarkers continues. Enrollment is complete, and pt treatment and follow-up are ongoing. [Table: see text] [Table: see text]

9068 Background: AP23573 (AP) is a non-produg rapamycin analog, which potently inhibits mTOR, a downstream effector of the PI3K/Akt pathway. AP has demonstrated some anti-tumor activity in sarcomas...

9028 Background: AP23573 (AP) is a non-prodrug rapamycin analog, which potently inhibits mTOR, a downstream effector of the PI3K/Akt pathway. AP has demonstrated some anti-tumor efficacy in sarcoma...