Activity In Soft Tissue Sarcoma Research Articles

Safety and Efficacy of the Combination Lurbinectedin plus Doxorubicin from a Phase 1b Trial in Patients with Advanced/Metastatic Soft-Tissue Sarcoma

Purpose: While cytotoxic chemotherapy is the standard first-line treatment for patients with metastatic soft-tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma and to further explore the safety profile and efficacy signal. Patients and Methods: Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3 + 3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1, 25 mg/m2 day 1; DL2, 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose and recommended dose for subsequent randomized trials. Results: Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were two dose-limiting toxicities (DLTs) at DL2 [day 8 (G2 alanine aminotransferase [ALT]/aspartate aminotransferase increase, G3 neutropenia)], and one DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median progression-free survival is 16.5 months [95% confidence interval (CI), 6.0–ND]. The objective response rate was 60% (6/10 confirmed partial responses). Conclusions: In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well tolerated and demonstrated intriguing clinical activity.

Selective DNA-PK Inhibition Enhances Chemotherapy and Ionizing Radiation Activity in Soft-Tissue Sarcomas.

Patients with advanced soft-tissue sarcomas (STS) exhibit a poor prognosis and have few therapeutic options. DNA-dependent protein kinase (DNA-PK) catalytic subunit is a multifunctional serine-threonine protein kinase that plays a crucial role in DNA double-strand damage repair via nonhomologous end joining. To investigate the therapeutic potential of DNA-PK targeting in STS, we first evaluated the prognostic value of DNA-PK expression in two large cohorts of patients with STS. We then used the potent and selective DNA-PK inhibitor AZD7648 compound to investigate the antitumor effect of the pharmacologic inhibition of DNA-PK in vitro via MTT, apoptosis, cell cycle, and proliferation assays. In vivo studies were performed with patient-derived xenograft models to evaluate the effects of AZD7648 in combination with chemotherapy or ionizing radiation on tumor growth. The mechanisms of sensitivity and resistance to DNA-PK inhibition were investigated by using a genome-wide CRISPR-Cas9 positive screen. DNA-PK overexpression is significantly associated with poor prognosis in patients with sarcomas. Selective pharmacologic inhibition of DNA-PK strongly synergizes with radiation- and doxorubicin-based regimen in sarcoma models. By using a genome-wide CRISPR-Cas9 positive screen, we identified genes involved in sensitivity to DNA-PK inhibition. DNA-PK inhibition deserves clinical investigation to improve response to current therapies in patients with sarcoma.

Redox status of blood lymphocytes in patients with soft tissue sarcomas

Introduction. The proven significance of free radical disorders in oncopathology determines the relevance of their study in soft tissue sarcomas (STS), which are characterized by a tendency to recurrence and high mortality of patients.Aim. To study the indicators of free radical oxidation and antioxidant protection in blood lymphocytes in primary and recurrent STS, depending on the sex and age of patients.Materials and methods. In 51 patients with primary STS, T2bN0M0 (17 men and 34 women) and in 34 patients (14 men and 20 women) with relapses, the level of lipid peroxidation products – malondialdehyde and diene conjugates, activities of superoxide dismutase and glutathione peroxidase, total peroxidase activity, the level of reduced glutathione were studied by spectrophotometric methods. Patients were divided by age: ≤45 years and >45 years. The comparison groups (donors) consisted of 12 men and 17 women divided into the same age subgroups.Results. In men >45 years old with primary sarcomas, there was an increase in diene conjugates by 2.2 times, with relapses by 2.4 times, and in young men - only with relapses by 2.6 times. The level of malondialdehyde in men did not change with primary sarcomas, with relapses it was reduced in both age groups by 2.4–2.6 times. In women with primary STS, there was an increase in most of the studied parameters in both age groups by 1.6–1.9 times. The increase in diene conjugates level and superoxide dismutase activity was the most pronounced (>3 times) in patients of the older age group. The increase in glutathione peroxidase activity in primary STS in young women was 2.3 times, and in the older age group in patients of both sexes it was 5 times. In half of the women with relapses developed no earlier than 3 years after treatment, a decrease in both lipid peroxidation products by 2.6–3.4 times was found, and in all women almost 4-fold activation of superoxide dismutase and 8-fold glutathione peroxidase with an increase in the level of reduced glutathione by 7 times took place, which was significantly higher than in men. For women of the older age group, a 3-fold increase in the ratio of superoxide dismutase/total peroxidase activity is characteristic for primary STS and almost 5-fold for recurrence.Conclusion. In primary STS, the activation of lipid peroxidation products and antioxidant enzymes in women is more pronounced than in men. Changes in most indicators are more typical for patients of older age groups, in which relapse was accompanied by a decrease in malondialdehyde in patients of both sexes and maximum activation of superoxide dismutase and glutathione peroxidase in women.

ENVASARC: A pivotal trial of envafolimab and envafolimab in combination with ipilimumab in patients with advanced or metastatic undifferentiated pleomorphic sarcoma or myxofibrosarcoma who have progressed on prior chemotherapy.

TPS11583 Background: Metastatic undifferentiated pleomorphic sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to first-line chemotherapy can approach 20%, efficacy remains limited in the 2nd-line setting and beyond. Pazopanib, the only FDA approved treatment in the refractory setting, has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered by rapid subcutaneous (SQ) injection that is approved for the treatment of microsatellite instability-high (MSI-H) cancer in China. The activity of envafolimab appears to be similar to other PD-1 antibodies administered intravenously (i.v.). Envafolimab demonstrated a 32% ORR in MSI-H colorectal cancer patients with progressive disease following three approved chemotherapeutics, similar to the ORR of 28% and 33% with nivolumab and pembrolizumab in these patients, respectively. The rationale for the ENVASARC is based on envafolimab activity in STS in phase 1 trials and previously reported activity of checkpoint inhibition in UPS/MFS: single-agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at 30 U.S. and U.K. centers) open-label, randomized, non-comparative, parallel cohort study of envafolimab 600 mg every 3 weeks by SQ injection (n = 80) or envafolimab 600 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks i.v. for four doses (n = 80) in patients with locally advanced, unresectable or metastatic UPS/MFS with disease progression on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed among the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response, PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy ([neo]adjuvant therapy excluded), ECOG ≤ 1. Clinical trial information: NCT04480502 .

A phase II study of surufatinib in patients with osteosarcoma and soft tissue sarcoma who have experienced treatment failure with standard chemotherapy.

e23540 Background: Surufatinib is a multi-targeted, small-molecule tyrosine kinase inhibitor (TKI) that shows strong inhibitory effect on the activity of VEGFR-1, 2, 3, FGFR1 and CSF-1R. Here we conducted this trial to explore the efficacy and safety of surufatinib in the treatment for osteosarcoma and soft tissue sarcoma (STS) patients (pts) who have failed in standard chemotherapy. Methods: Pts with advanced osteosarcoma and STS (unresectable or metastatic), 14-70 years, and ECOG PS 0-1, are eligible. Surufatinib 300 mg q.d. is given in a 21-days schedule. Progression-free rate at 12 weeks (PFR12weeks) was the primary endpoint. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety (NCT05106777). Results: As of December 30, 2022, 19 pts (male, n=12; median age, 44 years [range, 23-67]; median lines of prior therapy, 2 [range, 2-5]) were enrolled. The most common histological subtypes included 3 leiomyosarcoma, 3 liposacroma, 3 epithelioid hemangioendothelioma, 2 fibrosarcoma and other. The interim analysis revealed 7 pts with stable disease (SD) and 1 pt with partial response (PR) at 12 weeks in stage 1. Recruitment was continued in stage 2 as initially planned. With 15 pts for efficacy analysis, PFR12weeks was 60% (9 pts). Best objective response by RECIST 1.1 was complete response (CR) in 1 pt (ORR of 6.7%) and SD in 11 pts (DCR of 80%). With a median follow-up of 6.97 months (95%CI: 5.28-8.65), the median PFS was 5.7 months (95%CI: 1.07-10.30). Treatment emergent adverse events (TEAEs) were mostly mild (grade 1-2), and the most common were hypertension (80%), proteinuria (73%), hypertriglyceridemia (53%), diarrhea (47%) and hyperbilirubinemia (47%). Grade 3-4 TEAEs were recorded in 4 pts including hypertension, proteinuria, hypertriglyceridemia and hypermagnesemia. Conclusions: Surufatinib is well tolerated and have some clinical activity in advanced osteosarcoma and STS who failed standard chemotherapy. Enrollment is ongoing and updated data will be presented in the future. Clinical trial information: NCT05106777 .

1500P Radiochemotherapy with gemcitabine as a radiosensitizer in patients with soft tissue sarcomas

Radiation therapy is an essential backbone for the management of patients (pts) with soft tissue sarcomas (STS) as part of a multimodal curative or palliative treatment. Concurrent therapy with external-beam radiation therapy (EBRT) and chemotherapy with doxorubicin and ifosfamide is in use as well but is associated with relevant toxicity. Gemcitabine is a known radiosensitizer and shows activity in STS.

A phase I/II trial of the PD-1 inhibitor retifanlimab (R) in combination with gemcitabine and docetaxel (GD) as first-line therapy in patients (Pts) with advanced soft-tissue sarcoma (STS).

11516 Background: In a phase III trial, GD had similar response and survival rates to doxorubicin when administered as first-line therapy to advanced STS pts. G and D have each demonstrated synergy with PD-1 blockade in pre-clinical or clinical studies. We hypothesized that GD plus R would be safe, tolerable, and have synergistic activity in STS. Methods: This is an ongoing open-label, single-center, phase I/II trial of R (INCMGA00012) combined with GD in pts with treatment-naïve unresectable or metastatic high-grade STS. Herein, we report the phase I results, which included a safety run-in followed by a 3+3 dose de-escalation design. G (900 mg/m2) was administered on days 1 and 8 and D (75 mg/m2) on day 8, in 21-day cycles. R (210 mg IV flat dose on the run-in portion and 375 mg on the dose de-escalation portion) was administered on day 1 of each cycle starting in cycle 2 and continued as monotherapy after completion of 6 cycles of GD. The primary endpoint of the phase I was to determine the recommended phase 2 dose (RP2D) of R plus GD. Secondary endpoints included describing the safety, assessing best overall response rate (ORR) by RECIST 1.1, disease control rate (DCR), and progression-free survival (PFS). Results: Thirteen pts were treated, 7on the run-in and 6 on the de-escalation portion. One pt progressed prior to starting R and was replaced. Median pt age was 53 (range 28 – 74) and 7 were female. Histologies included leiomyosarcoma (n = 6), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (2), pleomorphic liposarcoma (1), angiosarcoma (1), and myxofibrosarcoma (1). The Table lists treatment-related adverse events (TRAEs) that occurred in ≥ 20% pts in descending order of frequency. Additional Grade (Gr) 3 TRAEs occurring in 1 pt each, included: infusion reaction, leukopenia, anorectal infection, neutropenia, and pyelonephritis. Gr 3 pyelonephritis was the only dose-limiting toxicity. There were no Gr ≥ 4 TRAEs. One pt (Gr 3 elevated AST/ALT) required corticosteroids and cessation of study therapy. The RP2D was determined to be 375 mg of R plus GD. Twelve pts were evaluable for response. ORR was 17% (1 of 6; 95% CI 1 - 64%) and 50% (3 of 6; 95% CI 19% - 81%) in the run-in and de-escalation cohorts, respectively. DCR was 100% (6 of 6; 95% CI 52 - 100%) and 83% (5 of 6; 95% CI: 36 - 99%). PFS rates at 24 weeks were 60% (95% CI: 29 - 100%) and 44% (95% CI: 17 - 100%). Conclusions: R plus GD was generally safe and well tolerated with no unexpected safety signals to date. The phase II portion evaluating efficacy of R plus GD at the RP2D is ongoing. Clinical trial information: NCT04577014. [Table: see text]

Gene expression analysis of sarcoma-infiltrating NK cells identifies signatures correlating with favorable prognosis and potential new targets for augmenting NK function

Abstract Success of current T-cell based immunotherapies in soft tissue sarcomas (STS) is limited while pre-clinical and clinical studies have shown evidence of NK activity in STS. To investigate the effects of the tumor microenvironment (TME) on tumor-infiltrating NK cell gene expression, we isolated circulating and tumor-infiltrating NK and CD3 T cells from sarcoma patients undergoing surgery (N=4) and performed RNA sequencing analysis. Comparing Differential Gene Expression (DGE) of flow-sorted intra-tumoral NK cells to circulating NK cells, we identified upregulation of genes involved in mitogen signaling inhibition (DUSP4) and metabolic function (SMPD3, SLC7A5), but not of genes typically associated with cytotoxic function (e.g. IFNG, GZMB). In contrast, intra-tumoral T cells showed significant upregulation of both activating (CD137) and inhibitory genes (TIM-3) compared to circulating T cells. We then queried the TCGA STS dataset and stratified cases into “NK Activating TME” and “NK Suppressing TME” based on the CIBERSORT NK signature analysis program (based on high or low proportion of activated NK cells, respectively). Patients with NK Activating TME had significantly improved survival compared to NK Suppressive TME (log-rank p = 0.03). DGE identified unique tumor-associated gene ontology between NK activated versus suppressive subsets with upregulation of the retinoic acid pathway. Unlike T cells which demonstrate significant DGE between circulating and tumor-infiltrating subsets, NK cells appear to have similar gene expression between blood and tumor. Therefore, although NK cells appear to be prognostic in STS, their anti-tumor effects may be dictated by systemic rather than local factors.

Radiochemotherapy with gemcitabine as radiosensitizer in patients with soft tissue sarcoma.

e23559 Background: Radiation therapy is an essential backbone of the management of patients (pts.) with soft tissue sarcoma (STS) as part of a multimodal curative or palliative treatment. Concurrent external-beam radiation therapy (EBRT) and chemotherapy with doxorubicin (doxo) and ifosfamide (ifo) may be indicated as well, but is associated with relevant toxicity. Gemcitabine (gem) is a known radiosensitizer and has shown activity in STS. The purpose of this study was to evaluate the efficacy and toxicity of concurrent EBRT and gemcitabine. Methods: A single center, retrospective analysis of 12 patients (pts) with STS treated with concurrent EBRT and gemcitabine from Nov 2017 to Dez 2019 in a neoadjuvant (6 pts) or palliative setting (6 pts). Gemcitabine (gem) was administered with 150-300mg/m2 once weekly for the duration of the EBRT (50 Gy in 25 fractions over 5 weeks). In the neoadjuvant treated group, 4 pts had undifferentiated pleomorphic sarcoma (UPS) G3, 1 leiomyosarcoma (LMS) G2 and 1 retroperitoneal G1 liposarcoma (LPS). The pts. were either not eligible for a neoadjuvant systemic treatment with doxo/ifo or received the EBRT/gem treatment in addition to it. Results: 5/6 pts. with neoadjuvant EBRT/gem had R0 resection and 1/6pt. R1. The IUCC stage was IIIB in 5/6 pts and IB in 1/6 pt. The tumor regression grade (TRG) was > 99% in 3/4 pts. with UPS G3 (75%) and 80% in 1/4 pt. with UPS G3. The TRG for the G2 LMS and for the G1 LPS was 20%. All pts treated in palliative setting had high grade sarcoma and responded to the treatment with partial remission, the 6 months’ local control rate was 83% (5/6 pts) for symptomatic fast growing lesions, 1/6 pt. being in PR at 4 months follow up. The combination treatment was well tolerated with reversible skin toxicity CTCAE grade I. As expected transient thrombocytopenia was observed without limiting effect on the planned EBRT. Conclusions: The combination therapy of EBRT and gemcitabine as sensitizer in pts. with STS is feasible und well tolerated. The treatment is an option for patients not eligible for neoadjuvant systemic treatment with doxo/ifo and in the palliative setting as well. It might be more potent than radiation only in achieving tumor regression and local control for high grade STS.

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

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

LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications.

Background: LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS). Methods: We analyzed the LRRC15 expression profile by immunohistochemistry in 711 STS cases, covering a broad spectrum of STS histologies and sub-classifications. In vivo experiments were carried out by using LRRC15-positive and LRRC15-negative patient-derived xenograft (PDX) models of STS. Results: In contrast to patterns observed in epithelial tumors, LRRC15 was expressed not only by stromal cells but also by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. Overexpression of LRRC15 is positively correlated with grade and independently associated with adverse outcome. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models. Conclusion: We provide the first preclinical evidence that LRRC15 targeting with an antibody-drug conjugate is a promising strategy in LRRC15-positive STS. ABBV-085 is being evaluated in an ongoing clinical trial in STS and other malignancies.

Ifosfamide, Carboplatin, and Etoposide (ICE) in Combination with Regional Hyperthermia as Salvage Therapy in Patients with Locally Advanced Nonmetastatic and Metastatic Soft-Tissue Sarcoma

Patients with localized relapse of soft-tissue sarcoma (STS) after anthracycline-based chemotherapy have a dismal prognosis, particularly when surgery is not possible. To facilitate resection and improve long-term tumor control, we applied an intensified perioperative treatment consisting of ICE (ifosfamide 6 g/m2, carboplatin 400 mg/m2, and etoposide 600 mg/m2) in combination with regional hyperthermia (RHT) to maximize local control. Here, we retrospectively evaluate the safety and efficacy of this strategy. Patients aged ≥18 years with locally advanced high-risk STS, either with or without metastasis, treated with ICE + RHT after the failure of first-line anthracycline-based chemotherapy were included in this analysis. Radiographic response, toxicity, progression-free survival (PFS), and overall survival (OS) were assessed. Between 1996 and 2018, 213 sarcoma patients received ICE at our centre. Of these, 110 patients met the selection criteria (progressive disease, suitable high-grade STS histology, anthracycline pretreatment, RHT treatment) for this analysis. Fifty-four patients had locally advanced disease without metastases (LA-STS), and 56 patients had additional metastatic disease (M-STS). Disease control was achieved in 59% of LA-STS patients and in 47% of M-STS patients. For LA-STS, 21% of the patients achieved radiographic response, facilitating resection in 4 patients (7%), compared with 11% of the M-STS patients, facilitating resection in 5 patients (9%). PFS was significantly longer in LA-STS than in M-STS (10 vs. 4 months, p < 0.0001). Median OS was 26 months in LA-STS and 12 months in M-STS. Disease control was the only independent prognostic factor for improved OS in multivariate analysis. Toxicity was high with neutropenic fever occurring in 25% of the patients and three therapy-related deaths (3%). ICE + RHT demonstrated activity in high-risk STS and facilitated resection in selected patients after anthracycline failure. Disease control was associated with improved OS. Based on the observed toxicities, the dose should be reduced to 75%.

1701P - Inhibition of mTOR signaling enhances trabectedin activity in soft tissue sarcoma

BackgroundSoft-tissue sarcomas (STS) are life-threatening diseases, for which more efficient therapeutic options are necessary. Trabectedin (T) is an anti-tumor drug approved for the treatment of advanced STS. Synergistic drug combinations could improve T results in STS patients. Rapamycin (R) is an mTOR pathway inhibitor. Synergy with T has been described in ovary clear cell carcinoma. Of note, R suppresses DNA double-strand breaks repair, thus generating the perfect set-up for T activity. Altogether, we hypothesize that T+R combination (T+R) is synergistic in STS, and that mTOR inhibition enhances T activity. MethodsHuman STS cell lines (n=9) were treated with increasing doses of T (1x10-7M to 1x10-11M) and/ or R (1x10-9 to 1x10-11) to determine IC50 and combination index (CI) values. Cells were initially exposed to R, 2hours later T was added, under the assumption that R pre-treatment favors T cytotoxicity. Cell viability, at 72h, was measured by MTS assay. Apoptosis was determined by Western Blot for PARP and Caspase 3 cleavage. In vivo experiments were performed in immunocompetent 3-methylcolanthrene fibrosarcoma mice: T was administrated via IV (0.15mg/kg; q7dx1) and R via IP (0.50mg/kg; q7dx2). Body weight and tumor volume were measured every 2 days for 15 days of treatment. Tumors were collected for analysis (snap frozen and paraffin embedding). ResultsT+R was synergistic in all STS cell lines: CP0024 primary leiomyosarcoma and 93T449 liposarcoma cell lines showed strong synergism with CI at the ED50 of 0.129 and 0.027, respectively. This synergy was followed by an increase of PARP and Caspase 3 cleavage. The synergism was confirmed in vivo: mice treated with R+T showed tumor growth delay in comparison to the drugs alone (p<0.05). Stable disease was achieved in 7 out of 7 mice. ConclusionsR+T is synergic in STS and deserves exploration in clinical setting. Further research will reveal the mechanisms underlying this synergy. Legal entity responsible for the studyJavier Martín Broto. FundingPharmaMar. DisclosureD.S. Moura: Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Eisai. M. Lopez-Alvarez: Travel / Accommodation / Expenses: Eisai. N. Hindi: Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): PharmaMar; Honoraria (self): PharmaMar. J. Martin-Broto: Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Honoraria (self): PharmaMar; Honoraria (self): Lilly; Honoraria (self): Novartis; Speaker Bureau / Expert testimony: PharmaMar. All other authors have declared no conflicts of interest.

1731TiP - EREMISS: Efficacy of regorafenib (REG) as maintenance therapy in non-adipocytic soft tissue sarcomas (STS) having received 1st-line doxorubicin-based chemotherapy (Doxo-CT)

BackgroundIn advanced STS, median progression-free survival (PFS) remains at 4 months (mo) and median overall survival (OS) is about 12-18mo after Doxo-CT. There is currently no maintenance therapy available. A phase III trial has shown a modest benefit of a maintenance with ridafolimus compared to placebo (PBO) (PFS, 17.7 vs 14.6 weeks, HR=0.72). REG is an orally bioavailable multikinase inhibitor with meaningful activity in doxorubicin-refractory non-adipocytic STS. In a prior randomized phase II trial (REGOSARC; NCT01900743), median PFS was 4.0mo with REG compared to 1.0 with PBO (HR=0.36, p<0.0001) and median OS was 13.4 vs 9.0mo (HR=0.67; p=0.059). Trial designEREMISS (NCT03793361) is a multicenter (17 centers from the French Sarcoma Group) double-blind controlled randomized phase II trial assessing efficacy and safety of REG compared to PBO as maintenance therapy in metastatic / locally advanced STS experiencing stable disease (SD) or partial response (PR) after 6 cycles of Doxo-CT as 1st-line. The primary endpoint is PFS (RECIST 1.1, centrally reviewed). Secondary endpoints are efficacy (OS, Objective response, time to start subsequent therapy), safety and benefit/risk ratio (Q-TWIST). The randomization is balanced 1:1 and controlled for histology (leiomyosarcoma/synovial sarcoma/other sarcoma), response to CT (SD/PR) and centers. Pts receive either REG (120mg/d 21/28 days) or PBO until unacceptable toxicity, progression or consent withdrawal. There is no cross-over in this trial. Main eligibility criteria are: age ≥18; histologically-proven non-adipocytic STS, metastatic / locally advanced STS not amenable to curative intent surgery, PS<2, measurable disease, SD or PR after 6 cycles of Doxo-CT. Based on the following assumptions: PFS, 7 (REG) vs 4mo (PBO), HR=0.57, 1-sided α=5% and β=10%, the required number of events is 110 and the sample size is 126 pts. The planned study duration is 30 months. Enrolment is open since 12/2018. Clinical trial identificationNCT03793361. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureA. Le Cesne: Honoraria (self): PharmaMar; Honoraria (self): Lilly; Honoraria (self): Novartis. All other authors have declared no conflicts of interest.

Phase 1b study of selinexor, a first-in-class selective inhibitor of nuclear export (SINE) compound, in combination with doxorubicin in patients (pts) with locally advanced or metastatic soft tissue sarcoma (STS).

3123 Background: Selinexor is a first-in-class SINE compound with single-agent activity in STS. We undertook this study to determine the safety, tolerability and efficacy of selinexor in combination with doxorubicin in pts with incurable STS. Methods: This phase 1b study was conducted using a bayesian model (modified toxicity probability index). Patients with locally advanced or metastatic STS received selinexor at either 60 or 80mg weekly PO plus doxorubicin (75mg/m2 IV q21 days, max 6 cycles). Pts with stable disease (SD) or better (per RECIST 1.1 criteria) after 6 cycles of combination treatment received selinexor monotherapy until disease progression or unacceptable toxicity. Disease assessments were made with standard imaging after every 2 cycles. Results: 24 pts (19F/5M, ECOG 0/1: 12/12, median age 58.5 years [range 34-74]) were enrolled. Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumor (n = 3) and other sarcomas (n = 15). Three pts at 60mg selinexor and 21 pts at 80mg selinexor were treated. The most common G3 drug related adverse events were hematological, neutropenia n = 13 (54%), anemia n = 6 (25%). There were 4 dose-limiting toxicities (2 febrile neutropenia, 1 vomiting and 1 unresolved fatigue) all at the 80mg dose level, but does not satisfy criteria for maximum tolerated dose. Two patients had clinically significant and relevant drop in ejection fraction, presenting with cardiac symptoms. Of the 24 evaluable pts 4 (17%) had a partial response, 16 (67%) had SD as best response and SD &gt; 16 weeks was seen in 13 pts (54%). PK analysis of selinexor did not demonstrate changes compared to single agent profile. The estimated median PFS and OS are 5.5 (95% CI:4.1-7.0) and 9.4 (6.6-13.8) months. Conclusions: Our initial data demonstrate that the combination of selinexor at 80mg with doxorubicin is tolerable and is associated with clinical benefit. Longer term follow up of available patients will be needed to understand toxicity profile. Clinical trial information: NCT03042819.

Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): Final results of SARC028 expansion cohorts.

11015 Background: Immune checkpoint inhibitors have demonstrated activity in multiple tumor types but their activity in soft tissue sarcomas remains limited. In the multicenter phase II study, SARC028, the anti-PD-1 antibody, P demonstrated objective responses that were largely restricted to UPS and LPS subtypes. We now report outcomes from 2 expansion cohorts of SARC 028 in advanced UPS and LPS. Methods: To further confirm the clinical activity of P in UPS and LPS, we enrolled an additional 30 pts in each of 2 expansion cohorts for a total of 40 UPS and 40 LPS pts. Primary endpoint was investigator-assessed response by RECIST v1.1. Secondary endpoints were safety, progression-free survival (PFS), 12-week PFS rate, and overall survival (OS). An ORR of 25% was considered clinically meaningful and &lt; 10% was considered to show lack of efficacy. P was to be considered a success if 8 or more of 40 enrolled patients had a PR or better (1-sided α = 0.042, 82% power). Pts age ≥18 with advanced, refractory UPS or LPS received 200 mg of P IV every 3 weeks until progression or unacceptable toxicity. Results: Preliminary results from the first 10 pts in each of the UPS and LPS cohorts have been reported. We now present summary data after enrolling an additional 30 pts in each cohort. The ORR in the UPS cohort was 23% (9/40), with an additional 5/30 PRs observed in the expansion cohort (total 2 CRs, 7 PRs). In the LPS cohort, the ORR was 10% (4/39 evaluable pts), with an additional 2/30 PRs observed (total 4 PRs). Median PFS for the UPS group was 3 months [95% CI: 2, 5] and 2 months [95% CI: 2, 4] for the LPS group. 12-week PFS rate was 50% in UPS [95% CI: 35, 65] and 44% in LPS [95% CI: 28, 60]. The UPS group had a median OS of 12 months [95% CI: 7, 34] and 13 months [95% CI: 8, NR] for the LPS group. P was well tolerated with no unexpected toxicities. Conclusions: The UPS cohort achieved its primary endpoint, however the activity of P in UPS deserves further evaluation in a randomized study. The activity of P was not confirmed in the LPS cohort. Ongoing biomarker analyses may direct better patient selection and guide future combination strategies. Clinical trial information: NCT02301039.

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

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

Design, Synthesis, and Characterization of Globular Orphan Nuclear Receptor Regulator with Biological Activity in Soft Tissue Sarcoma.

Sarcomas are rare and heterogeneous cancer variants of mesenchymal origin. Their genetic heterogeneity coupled with uncertain histogenesis makes them difficult to treat and results in poor prognosis. In this work, we show that structure-based drug discovery involving computational modeling can be used to identify a new retinoid X receptor (RXR) agonist ligand with a bis(indolyl)methane scaffold. This agent co-self-assembles with an amphiphilic diblock copolymer resulting in nanoparticles (Nano-RXR) with excellent kinetic stability, which were evaluated for efficacy and safety in transformed sarcoma cells, 63-3 Cre and 141-10 Cre of pig origin, and in rodent xenograft models. Responses at gene and protein levels established the treatment approach as a highly effective RXR agonist across cell, rodent, and "Oncopig" models. Interestingly, Nano-RXR was not only able to modulate metabolic and transporter genes related to orphan nuclear receptors but also played a major role in modulating programmed cell death in sarcomas developed in Oncopigs.

Aldoxorubicin therapy for the treatment of patients with advanced soft tissue sarcoma.

Soft tissue sarcomas are a group of rare tumors of mesenchymal origin, and account for less than 1% of all cancers. The most commonly used drug for the treatment of soft tissue sarcoma is anthracycline chemotherapeutic agent, doxorubicin. The major limitation for doxorubicin is cardiotoxicity. Hence, to overcome this limitation and to increase efficacy, aldoxorubicin was developed, which has demonstrated activity in soft tissue sarcomas without much cardiotoxicity. In this review article, we discuss mechanism of action, pharmacokinetics, preclinical studies, clinical trial data and safety profile of aldoxorubicin and its potential applicability in the future of sarcoma treatment.

Phase 1b study of selinexor, a first in class selective inhibitor of nuclear export (SINE) compound, in combination with doxorubicin in patients (pts) with locally advanced or metastatic soft tissue sarcoma (STS).

3123Background: Selinexor is a first-in-class SINE compound with single-agent activity in STS. We undertook this study to determine the safety, tolerability and efficacy of selinexor in combination...