Abstract Introduction: IL-12 is a potent multifunctional regulator of cell-mediated immunity that activates NK, NKT, Th1, and CTL cells to produce IFNγ and efficiently kill tumor cells in mice, yet clinical studies of rhIL-12 at the MTD of 500 ng/kg have failed to show adequate benefit. Single-chain native IL12 linked to a fully-human albumin binding (FHAB®) scFv domain (SON-1010) provides enhanced targeting and retention of the cytokine in the tumor microenvironment (TME) through albumin binding to locally over-expressed FcRn, GP60, and SPARC, with an improved PK profile and broader therapeutic index. SON-1010 was given as monotherapy in the dose-escalation portion of study SB101 in advanced solid tumors and 1 patient had a PR at the maximum dose of 1200 ng/kg. In the second part of this study, SON-1010 was used with trabectedin (Yondelis®) in metastatic soft-tissue sarcoma (STS). Trabectedin, a DNA-binding chemotherapy, is approved as 2nd line in unresectable or metastatic STS and is associated with a median PFS of 4.2 months. It also activates macrophages toward a pro-inflammatory phenotype in the TME. Methods: SB101 is a first-in-human Phase 1 study that initially assessed the safety, PK, PD, and efficacy of SON-1010 dosed SC every 3 weeks using a 3+3 design (NCT05352750). A relatively low desensitizing 1st dose of SON-1010 activates the tachyphylaxis associated with IL-12, followed by higher maintenance doses in each cohort. Safety was reviewed in each group before dose escalation. An expansion cohort was enrolled that alternated trabectedin with SON-1010 at 1200 ng/kg in 3 week cycles. This cohort was designed to establish benefit using a Simon 2-stage approach with α of 0.1 and 80% power in 18 patients with STS. The first stage required at least one of the first 7 patients to show clinical benefit, defined as a RECIST response or stable disease (SD) at 4 months. The second stage required at least 4 patients to show the same. Results: All adverse events (AEs) have been transient and dosing was well tolerated; most have been mild or moderate. There were no dose-limiting toxicities and no patients were discontinued due to related AEs. The most common AEs considered related to SON-1010 were fatigue, fever, chills, and myalgia. Fourteen of the 18 patients (78%) in the combination cohort had clinical benefit at 4 months, including 1 confirmed PR. Eight patients have progressed to date and one stopped due to surgery. Nine patients remain on study, so the median PFS has not yet been reached; the mean PFS is currently 6.9 months. Conclusion: SON-1010, an extended half-life version of rhIL-12 that targets the TME, acts safely and synergistically with trabectedin to augment the potential for tumor control in STS, addressing a significant unmet medical need. The responses achieved with monotherapy or in combination could increase with higher doses. SON-1010 may act by immunologically ‘warming’ the TME to improve the effectiveness of trabectedin in extending the PFS. Citation Format: Sant Chawla, Victoria Chua, Neal Chawla, Erlinda M. Gordon, John Cini, Richard Kenney. SON-1010 (IL12-FHAB) synergizes with trabectedin in advanced soft-tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT179.

BACKGROUND:Ontorpacept, a recombinant signal regulatory protein alpha (SIRPα)-blocking fusion protein, has antitumour activity by disrupting CD47-SIRPα signalling. This Phase 1/2 study examined ontorpacept with doxorubicin in patients with leiomyosarcoma. METHODS:Eligible patients were ≥18 years with metastatic or locally advanced high-grade soft-tissue sarcomas (high-grade leiomyosarcoma in Phase 2). In Phase 1, patients received escalating doses of ontorpacept plus doxorubicin. Phase 2 dose expansion evaluated ontorpacept doses 0.2, 1.0, and 2.0 mg/kg plus doxorubicin. The primary endpoints were safety (Phase 1); and objective response rate (ORR) (Phase 1/2). RESULTS:Seventy-six patients were enrolled (Phase 1, n = 9; Phase 2, n = 67). No dose-limiting toxicities occurred in Phase 1. The most common treatment-related adverse events were neutrophil count decreased/neutropenia (grade ≥3 in 66% of patients). In Phase 1, one patient receiving ontorpacept 2.0 mg/kg had a confirmed partial response. In Phase 2, six patients receiving ontorpacept 0.2 mg/kg (ORR, 18.8%; 95% CI, 7.2-36.4) and one patient receiving 2.0 mg/kg (ORR, 4.5%; 95% CI, 0.1-22.8) had confirmed partial responses. CONCLUSIONS:This first study of CD47 inhibition with chemotherapy in leiomyosarcomas shows manageable safety, supporting further investigation of ontorpacept dosing and schedule, in combination with doxorubicin and as monotherapy.

Abstract Background: Advanced angiosarcoma is a rare and aggressive sarcoma which is most often fatal, with a median progression free survival of 4-6 months on standard therapy. Therefore, innovative treatment regimens are urgently needed. Methods: Endpoints: Primary: Progression Free Survival; Secondary: Best overall response; Overall Survival; Incidence and severity of adverse events. Eligibility: > 18 years, confirmed diagnosis of advanced angiosarcoma, acceptable hematologic and organ function. Treatment Schedule: Gemcitabine (600 mg/m2; max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Days 1 and 8, and nivolumab (240 mg) on Day 1 of a 3-week cycle. Results: Median prior regimens = 1 (range 0-9). Efficacy: 7 of 9 patients who completed at least 2 treatment cycles and follow-up imaging (modified ITT population) were evaluated for: Median PFS: 9.4 months (95% CI: 8.224 to 9.441; 7 events, 0 censored); Best response: Confirmed 1 CR, 3 PR, 3 SD; ORR = 57%; DCR = 100%. Nine patients who received at least one dose of each chemotherapy agent (ITT population) were evaluated for: Median OS: 28.4 months (95% CI: 0.724 to 31.217; 5 events, 4 censored). Safety: 8 of 9 (89%) patients experienced a ≥ Grade 3 TRAE: leukopenia (n=6), thrombocytopenia (n=4), neutropenia (n=5), anemia (n=2), lymphopenia (n=2), fatigue (n=1), dec. LVEF (n=1), periorbital edema (n=1), limb edema (n=1) and worsening hypothyroidism (n=1). There were no Grade 5 nor unexpected adverse events. Conclusion: This metronomic chemo/immunotherapy regimen may be a synergistic and effective therapy for advanced angiosarcoma with manageable toxicity. Citation Format: Samantha Jeffrey, Piya Mann, Oliver Davidorf, Anmol Dia Agarwal, Sarah Lande, Mihir Chawla, Neal Chawla, Ania Moradkhani, Ted Kim, Victoria Chua-Alcala, Sant Chawla, Erlinda Gordon. A Phase II chemo/immunotherapy study using metronomic gemcitabine, doxorubicin, docetaxel and nivolumab for advanced angiosarcoma (NCT04535713): An interim analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT256.

Abstract Background: Advanced angiosarcoma is a rare and aggressive sarcoma which is most often fatal, with a median progression free survival of 4-6 months on standard therapy. Therefore, innovative treatment regimens are urgently needed. Methods: Endpoints: Primary: Progression Free Survival; Secondary: Best overall response; Overall Survival; Incidence and severity of adverse events. Eligibility: > 18 years, confirmed diagnosis of advanced angiosarcoma, acceptable hematologic and organ function. Treatment Schedule: Gemcitabine (600 mg/m2; max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Days 1 and 8, and nivolumab (240 mg) on Day 1 of a 3-week cycle. Results: Median prior regimens = 1 (range 0-9). Efficacy: 7 of 9 patients who completed at least 2 treatment cycles and follow-up imaging (modified ITT population) were evaluated for: Median PFS: 9.4 months (95% CI: 8.224 to 9.441; 7 events, 0 censored); Best response: Confirmed 1 CR, 3 PR, 3 SD; ORR = 57%; DCR = 100%. Nine patients who received at least one dose of each chemotherapy agent (ITT population) were evaluated for: Median OS: 28.4 months (95% CI: 0.724 to 31.217; 5 events, 4 censored). Safety: 8 of 9 (89%) patients experienced a ≥ Grade 3 TRAE: leukopenia (n=6), thrombocytopenia (n=4), neutropenia (n=5), anemia (n=2), lymphopenia (n=2), fatigue (n=1), dec. LVEF (n=1), periorbital edema (n=1), limb edema (n=1) and worsening hypothyroidism (n=1). There were no Grade 5 nor unexpected adverse events. Conclusion: This metronomic chemo/immunotherapy regimen may be a synergistic and effective therapy for advanced angiosarcoma with manageable toxicity. Citation Format: Oliver Davidorf, Sarah Lande, Samantha Jeffrey, Anmol Dia Agarwal, Piya Mann, Allyssa Lingad, Alex Borsada, YuJeong Yoon, Mihir Chawla, Halu Kauffman, Michael Siriprabrydhi, Stephanie Melchor, Neal Chawla, Ania Moradkhani, Ted Kim, Victoria Chua-Alcala, Sant Chawla, Erlinda Gordon. A Phase II chemo/immunotherapy study using metronomic gemcitabine, doxorubicin, docetaxel and nivolumab for advanced angiosarcoma (NCT04535713): An interim analysis [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-B006.

Background Arginine deprivation with pegylated arginine deiminase (ADI-PEG 20, pegargiminase) may enhance chemotherapy efficacy in soft tissue sarcomas (STS). We conducted a phase II trial (NCT03449901) evaluating ADI-PEG20 plus gemcitabine/docetaxel in advanced STS. Methods Seventy-five evaluable patients received ADI-PEG20 with gemcitabine/docetaxel across three dose cohorts. Correlative analyses included immunogenicity, transcriptomics, and metabolomics for a subset of patients. Results Median PFS was 4.03 months and OS was 18.83 months, with a clinical benefit rate of 66.2%. Clinical benefit was preserved across gemcitabine/docetaxel dose cohorts, including the reduced-dose 600/60 mg/m² cohort selected after protocol-directed safety monitoring. Transcriptomics revealed MYC pathway enrichment in treated tumors. Metabolomics confirmed arginine depletion with compensatory glutamine anaplerosis and increased nucleotide turnover. Conclusions ADI-PEG20 plus gemcitabine/docetaxel demonstrates clinical activity in advanced STS. Correlative analyses provide the first clinical validation of arginine deprivation-induced metabolic reprogramming, supporting combination strategies targeting compensatory metabolic pathways.

TPS11588 Background: Soft tissue sarcomas (STS) are a rare and diverse set of tumors. Systemic chemotherapy provides limited benefit for metastatic disease. INT230-6 is a novel formulation of cisplatin (CIS) and vinblastine (VIN) with a tissue dispersion enhancer (SHAO). The drug’s unique chemistry permits dispersion throughout tumors and diffusion into the cancer cells after IT injections. The drug causes apoptosis and recruits T-cells to the tumor. An open-label, phase 1/2 study was completed with locally advanced, unresectable, or metastatic adult patients with 11 STS subtypes. Patients had a median of 3 prior lines. Biopsied tissue from pre- and post-dosed tumors 2 showed immune engagement post-dose. PK data showed that >95% of VIN stayed in the tumor. There were no dose-limiting toxicities up to 175 mL (87.5 mg CIS, 17.5 mg VIN). The disease control rate was 93%. Uninjected tumors shrank. The median OS for INT230-6 alone (n=15) was 21.3 CI (4.7, NR) months. The maximum severity of INT230-6 treatment-related adverse events (TRAEs) in STS patients was 6.7% grade 1, 60% grade 2, and 33% grade 3 (no related grade 4 or 5 AEs). The most common TRAEs were pain, fatigue, and nausea. Methods: IT-03 is a 2:1 randomized trial comparing INT230-6 as monotherapy to an investigator’s choice of pazopanib, trabectedin, or eribulin, per label. A total of 333 patients in 2L/3L will be enrolled in the US, Canada, Europe, and Australia. INT230-6 dose is set by tumor size. INT230-6 is given IT Q2W for up to 5 doses to as many tumors >1 cm as is deemed safe. Maintenance is Q12 weeks for up to 22 months. Statistics: 90% power to detect a survival HR of 0.65 with 3 interim assessments at 20%, 40%, and 60% of participants events (deaths). The final analysis is at 80% of events. There is a two-sided total alpha = 0.05, allocated as follows: interim #1 = 0.0039; #2 = 0.0184; final = 0.043. Includes up to 60 sites: several sites are now recruiting. Inclusion criteria: Must be ≥ 18 yo, and provide written consent, Proven, unresectable, locally advanced, or metastatic STS; Must have received at least one line of therapy and progressed after anthracycline therapy. 1 tumor for injection of at least 2 cm. Adequate organ function in screening; lab values of: Neutrophils ≥ 1500/μL (≥ 1.5× 10 9 /L). PT, and INR ≤ 1.5× ULN, platelets ≥ 100,000/μL; hemoglobin ≥ 9 g/dL. Criteria must be met without erythropoietin dependency or packed red blood cell transfusion within last 2 weeks. Creatinine normal; or clearance > 50 mL/min by the C-G equation. ALT SGOT/ AST SGPT ≤ 2.5× ULN without, and ≤ 5× ULN with hepatic metastases. Bilirubin (BR) ≤ 1.5× ULN (except those with Gilbert’s syndrome, who must have total BR ≤ 3.0 mg/dL [< 52 µmol/L]). CPK ≤ 2.5× ULN. Clinical trial information: NCT06263231 .

In the phase III placebo-controlled DeFi trial (ClinicalTrials.gov identifier: NCT03785964) primary analysis, nirogacestat showed significant improvement versus placebo in progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PRO) in adult patients with progressing desmoid tumors (DT; median [range] exposure: 20.6 [0.3-33.6] months). Here, long-term nirogacestat efficacy and safety were evaluated in patients randomly assigned to nirogacestat and followed through the final data cutoff date of December 19, 2024. End points included PFS and ORR per RECIST v1.1, PRO, and safety. The median (range) duration of exposure was 33.6 (0.3-61.8) months. Median PFS was not reached. The ORR with up to 4 years of nirogacestat treatment was 45.7% (32 of 70), with three additional partial and three additional complete responses since the primary analysis. Further target tumor size reduction occurred in most patients. Benefits in PROs were sustained while on treatment. Frequently reported treatment-emergent adverse events (TEAEs) decreased in incidence and severity over time. Since the primary analysis, four patients discontinued nirogacestat because of TEAEs between years 2 and 4. In conclusion, long-term continuous nirogacestat treatment was associated with further tumor size reductions, durable objective responses, sustained PRO benefits, and a manageable safety profile consistent with the primary analysis.

Introduction This was the first phase 1 study conducted in the United States. It consisted of dose-escalation (part A) and multiple indication-specific cohort expansion (part B), investigating the safety and preliminary efficacy of toripalimab (anti–programmed cell death-1 inhibitor) in patients with advanced malignancies. Methods Patients with advanced malignancies that progressed after treatment with at least one prior line of standard systemic therapy, including the patients with advanced/recurrent cholangiocarcinoma (CCA), received toripalimab 240 mg every 3 weeks in part B. The primary endpoint was safety assessment. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) as assessed by the investigators according to Response Evaluation Criteria in Solid Tumors (version 1.1) and overall survival (OS). Results In part B, 166 patients, including the 42 patients with CCA, were enrolled and received toripalimab. Among the 166 patients, treatment-emergent adverse events (TEAEs) of any grade occurred in 158 (95.2%) patients, and 97 (58.4%) patients experienced TEAEs of Grade 3 or greater. The most common TEAE was fatigue (42.2%). Seven (4.2%) patients experienced TEAEs with a fatal outcome, none of which were identified by investigators as related to toripalimab. Investigator-assessed immune-related adverse events (irAE) of Grade 3 or higher occurred in 7 (4.2%) patients. In the CCA cohort, with the median follow-up of 4.4 months, the ORR and DCR were 4.8% (95% CI: 0.58, 16.16) and 40.5% (95% CI: 25.63, 56.72), respectively; median DoR was 7.8 (range 4.4+ to 7.8) months; median PFS was 2.1 (95% CI: 1.91, 3.88) months; median OS was not estimable. Conclusions Toripalimab had manageable side effects in patients with refractory cholangiocarcinoma and exhibited preliminary evidence of anti-tumor activity. However, further information regarding biomarkers is needed. ClinicalTrials.gov ID: NCT03474640

11561 Background: Liposarcoma (LPS) is characterized by unstable genomes and high occurrence of gene fusions. Hotspots of both recurrent and non-recurrent gene fusions can provide information about structural alterations in certain LPS subtypes. For instance, myxoid (M) LPS expresses the oncogenic FUS-DDIT3 protein and is known to be fusion-driven. Moreover, disrupted locus 12q13-15 is an important feature of well-dedifferentiated (WD) and dedifferentiated (DD) LPS, and is the site of copy number alterations (CNAs) and gene fusions. Here, we used RNA sequencing to uncover hotspots of intra- and transchromosomal gene fusions in LPS patient samples, identifying potentially clinically relevant events in certain chromosomal regions. Methods: The BostonGene internal LPS cohort (n=150) was analyzed by bulk whole-transcriptome sequencing, using STAR-fusion for sequence calling. Quality control was performed using FastQC, FastQ Screen, RSeQC, and MultiQC. Tumor purity was assessed via pathological and bioinformatics examination with a threshold of 20%. One sample Poisson rate test was used to evaluate statistical significance of gene fusion hotspots. Results: We identified 4,080 gene fusions among four LPS subtypes (DDLPS, WDLPS, MLPS, and PLPS - pleomorphic LPS). Of those, 2,302 (56.4%) were intrachromosomal and 1,778 (43.6%) were transchromosomal. Over half of these fusions (1,263/2,302 intrachromosomal fusions, 54.9%; 1,047/1,778 transchromosomal fusions, 58,9%) were detected on chromosome 12. Most identified fusions occurred in the 12q13-15 region (q-value < 0.001), with q15 being especially prevalent in transchromosomal fusions (q-value < 0.001). The most prevalent recurrent fusion across our LPS cohort was FUS-DDIT3 (N=21, MLPS samples). Another notable recurrent fusion was TRIO-TERT (N=4, DDLPS). We also identified extended gene fusion hotspots in regions containing important oncogenes such as MDM2 and FRS2 in LPS subtypes (DDLPS, WDLPS, PLPS) that are not considered fusion-driven (Table). These findings suggest an oncogenic role of such fusions in these LPS subtypes, along with known CNAs like MDM2 amplification. Conclusions: Our comprehensive transcriptomic analysis of gene fusions in LPS samples uncovered both new and established hotspots of chromosomal rearrangements. Identification of such hotspots improves our understanding of LPS oncogenesis and thus can enhance the diagnostic accuracy and discovery of new biomarkers. Hotspots of gene fusions in liposarcoma. Hotspot cytoband Diagnosis q-value Important genes 1q23.3 DDLPS < 0.001 ATF6 1q24.3 DDLPS, WDLPS < 0.001 DNM3 12q13.3 MLPS < 0.001 DDIT3 12q14.1 DDLPS, WDLPS < 0.001 CDK4 12q14.3 DDLPS, WDLPS < 0.001 HMGA2, YEATS4 12q15 DDLPS, WDLPS, PLPS < 0.001 MDM2, FRS2, CPM 16p11.2 MLPS < 0.001 FUS

2013 Background: Isocitrate dehydrogenase (IDH) 1 or IDH2 mutations or co-mutations have been associated with various tumors, including glioma. HMPL-306 (’306) is a novel, small-molecule, orally available, highly selective, and potent dual inhibitor of both mIDH1 and mIDH2. This is a phase 1 study of ’306 in pts with locally advanced or metastatic solid tumors with mIDH. Here, we report the results of the dose escalation stage. Methods: Pts with locally advanced or metastatic solid tumors with any mIDH were enrolled to receive ’306 once daily (QD) for 28-day cycles. The mTPI-2 design was used for dose escalation, having explored in 8 successive cohorts (50-400 mg). The study aims to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), evaluate safety, tolerability, preliminary efficacy and pharmacokinetics/ pharmacodynamics (PK/PD). Results: As of Aug 9, 2024, 42 pts were administered ’306 across 8 doses (n = 3, 3, 5, 12, 6, 4, 4, 5 in 50, 100, 150, 200, 250, 300, 350, 400 mg QD cohorts, respectively), with 17 (40.5%) lower-grade glioma (LGG, grade 2 and grade 3 glioma) pts, 3 (7.1%) grade 4 glioma pts and 22 (52.4%) non glioma pts. The median age was 55 years, and 25 (59.5%) pts were male. During the dose escalation from 50 mg to 400 mg QD cohort, 1 pt given 250 mg QD experienced a dose-limiting toxicity (DLT) of grade 3 lipase increased. MTD was not reached. 12 (28.6%) pts reported grade ≥3 adverse events (AEs), which reported in ≥ 2 pts was abdominal pain. Efficacy signals were observed especially in LGG pts, in the efficacy evaluated set (N = 14), objective response rate (ORR) was 7.1%, disease control rate was 100%; in the safety analysis set (N = 17), median progression-free survival (PFS) was 20.5 months (95% confidence interval [CI]; 5.5-not estimable). One grade 2 glioma pt with multiple previous treatment on the 200 mg QD achieved minor response lasting 16.8 months. The ORR of grade 4 glioma pts and non glioma pts were not reached, the disease control rate were 33.3% and 25%, respectively. Drug exposures were dose-proportional from 50 mg to 400 mg. Steady-state with ~5-fold accumulation was reached after ~28 days of repeated daily dosing. In non-glioma pts, 2-HG inhibition plateaued after ~28 days, increasing with dose, reaching ~90% at ≥150 mg at C2D1. Conclusions: ’306 was well-tolerated in pts with mIDH1/2 solid tumors, showing target inhibition and durable responses in LGG. Clinical trial information: NCT04762602 .

e23560 Background: Advances in gene therapy/immunotherapy present the opportunity to further improve established treatment combinations for soft tissue sarcoma. Here, we present the results of a phase 2 study combining the chemo-immunotherapy regimen of intravenous Trabectedin (T) and Nivolumab (N), with intratumoral Talimogene Laherparepvec (TVEC), a genetically modified Herpes simplex Type 1 oncolytic virus expressing GM-CSF, which evokes a cytotoxic immune response. Methods: Objectives: Primary: To assess progression-free survival (PFS); Secondary: (1) To evaluate the best overall response (BOR) by RECIST v1.1, disease control rate (DCR), 6 month PFS rate, 6 month overall survival (OS) rate, and Incidence of treatment-related adverse events (TRAEs). Key eligibility criteria: ≥ 18 years, locally advanced unresectable or metastatic LMS/LPS, measurable disease by RECIST v1.1, at least one accessible tumor for TVEC intratumoral injection; adequate hematologic and organ function; no concurrent clinical trial; no known hypersensitivity to study drugs; no known autoimmune disorder. Study Design: This is an open label single center phase 2 study. Treatment schedule: N (240 mg i.v. q 2 weeks), T (1.2 mg/m2 i.v. q 3 weeks), and TVEC (1x10e8 PFU intratumorally q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x10e 6 PFU) was initially given, followed by a dose of 1x10e8 PFU q 2 weeks (according to tumor size) three weeks after the test dose. Results: Efficacy: The modified-intention-to-treat population (n=24), which includes patients who completed at least one treatment cycle and had a follow-up CT/MRI was used. Median PFS = 8.0 (95% CI: 4.1- 17.8) months; BOR = 2 PR, 18 SD, 4 PD; DCR = 83.3%; 6 month PFS rate = 62.5%; 6-month OS rate = 87.5%. Safety: The intention-to-treat population (n=35), which includes patients who received at least one dose of T, N, and TVEC, was used to determine safety and overall survival. Median OS = 19.2 (95% CI: 10.2- 37.9) months. Eighteen of 35 patients (51%) experienced Grade 3 TRAEs that included anemia (n=4), fatigue (n=3), ALT increased (n=3), AST increased (n=3), thrombocytopenia (n=3), abdominal pain (n=2), myalgia (n=2), localized edema (n=2), injection site pain (n=2), alkaline phosphatase increased (n=1), LVEF decreased (n=1), pain in extremity (n=1), neutropenia (n=1), colitis (n=1), headache (n=1), flu-like symptoms (n=1). There were no ≥ Grade 4 or unexpected adverse events. Conclusions: Taken together, the results indicate that the combination regimen of Talimogene laherparepvec, Nivolumab, and Trabectedin may be more effective than Trabectedin alone (Median PFS 4.1 months) as treatment for previously treated patients with advanced leiomyosarcoma and liposarcoma with manageable toxicity. A randomized phase 2 clinical trial is warranted to confirm these promising results. Clinical trial information: NCT03886311 .

TPS517 Background: High-copy number amplifications of oncogenes (e.g., EGFR , FGFR2 ) frequently occur on extrachromosomal DNA (ecDNA), highly transcribed units of circular non-chromosomal DNA. While targeted therapies have improved survival for patients with oncogene mutations, they have limited activity in oncogene amplified cancers. In Barrett’s esophagus-associated esophageal adenocarcinoma (EAC) ecDNA can be found early in the transition from high-grade dysplasia to EAC. In EAC and gastric cancer (EGC), ~7% and ~3% have EGFR and FGFR2 amplifications, respectively, with possibly >50% occurring on ecDNA. Tumor cells with oncogene amplifications, particularly on ecDNA, have increased DNA replication stress and are sensitive to inactivation of checkpoint kinase 1 (CHK1). We developed BBI-355, an oral, potent, and selective small molecule inhibitor of CHK1, which is in Phase 1/2 clinical development. Methods: BBI-355-101 is a first-in-human Phase 1/2 study of BBI-355 alone or in combination with targeted therapies for advanced or metastatic solid tumors with oncogene amplification (NCT05827614). Part 1 is dose escalation of BBI-355 (PO Q2D). In Parts 2 and 3, patients with EGFR or FGFR 1-3 amplifications are treated with BBI-355 in combination with the EGFR inhibitor erlotinib (150 mg PO QD) or the FGFR inhibitor futibatinib (20 mg PO QD). While this study is enrolling all tumor types, EGC are some of the most likely to harbor ecDNA amplifications. Amplification-driven cancers rarely contain driver oncogene mutations or fusions, and so are excluded. Results: Preclinical: Tumors that harbor oncogene amplifications on ecDNA can evade targeted therapeutic pressure via ecDNA-based resistance mechanisms. BBI-355 in combination with agents targeting the amplified oncogenes ( FGFR2 or EGFR ) prevented resistance to targeted therapies in multiple ecDNA+ gastric cancer CDX and PDX models. Clinical: Safety and PK data of BBI-355 alone and in combination with erlotinib or futibatinib will be presented. The most common drug-related TEAEs, SAEs, and DLTs were hematologic (i.e., leukopenia, neutropenia, lymphopenia and thrombocytopenia) which are on target for CHK1 inhibition and generally well managed. Dose escalation is ongoing and the RP2D/MTD has not been determined. PK showed dose-dependent increase in exposure of BBI-355. Target engagement as determined by pCHK1 IHC as a PD biomarker was observed at all dose levels of BBI-355. Conclusions: The first ecDNA directed therapy, BBI-355, demonstrated significant synergistic anti-tumor activity in combination with targeted therapies in multiple ecDNA+ oncogene amplified EGC models. BBI-355 alone and in combination with erlotinib/futibatinib was well tolerated. Clinical testing in patients with EGFR and FGFR2 oncogene amplifications is ongoing with a strong rational for EGC. Clinical trial information: NCT05827614 .

Previous phase I/II trials indicate promising activity of lurbinectedin plus doxorubicin (DOX) in leiomyosarcoma (LMS). We describe here the rationale and design of SaLuDo, an open label, randomized, multicenter, seamless phase IIb/III study to evaluate the antitumor activity and safety of lurbinectedin plus DOX versus DOX alone in the first-line setting of metastatic LMS. The phase IIb stage will evaluate two schedules of the combination for the phase III stage given every 3 weeks (q3wk): DOX 50 mg/m2 plus lurbinectedin 2.2 mg/m2, and DOX 25 mg/m2 plus lurbinectedin 3.2 mg/m2. The control arm will be DOX 75 mg/m2 q3wk. The primary endpoint is progression-free survival by independent review; overall survival is the key secondary endpoint. Clinical trial registration: www.clinicaltrials.gov identifier is NCT06088290.

TPS1136 Background: Metastatic breast cancer is almost always fatal. Objectives: Primary: To evaluate the safety of BC1 cell line immunotherapy in patients with advanced late-stage metastatic breast cancer; Secondary: To evaluate the tumor response to BC1 cellular immunotherapy; Exploratory: To evaluate progression-free (PFS) and overall survival (OS); To evaluate the immune responses elicited by BC1 cellular immunotherapy; To evaluate patient and tumor characteristics that may be predictive of responses to HLA-matched cellular immunotherapy; To evaluate time to subsequent therapy; and To evaluate PFS 2 on subsequent therapy. Methods: Study Population: Patients with metastatic recurrent breast cancer after progression on prior therapies. Key Inclusion Criteria: Histologically-confirmed metastatic breast cancer after failure of standard therapies; ≥18 years old; Expected survival of >4 months; Adequate performance status (ECOG ≤2); Adequate hematologic and organ function; Clinically stable with resolution of toxicities from previous treatment to baseline with the exception of alopecia. Key Exclusion Criteria: Concurrent anti-cancer treatment or concurrent cancer; Anti-cancer treatment within 3 weeks of first treatment; History of hypersensitivity to study therapies; New York Heart Association stage 3-4 cardiac disease; Moderate-severe pleural or pericardial effusion; Pregnant or nursing; HIV+; Known immunodeficiency or ongoing treatment with immunosuppressive therapy >10 mg/day prednisone equivalent; Severe psychiatric or other clinically progressive major medical problems. Study Design: This is an open-label study. Phase 1: BC1 cell line alone; Phase 2, Bria-OTS regimen with check point inhibitor (CPI). Phase 1: Patient 1: 20 million cells BC1 intradermally q2 wks x 8 wks (4 doses); Patient 2: 40 million cells of BC1; Patient 3: 60 million cells BC1. If no DLT with BC1 monotherapy, the combinational phase of the study will begin with BC1 and the Bria-OTS regimen q3 wks + CPI. During the Phase 1 combination and Phase 2 expansion phases, all patients will be treated with BC1 cells as part of the Bria-OTS regimen, which includes cyclophosphamide 300 mg/m 2 2-3 days prior to BC1 cell inoculation, and concurrent peg-interferon 0.6 mcg s.c. on the day of BC1 cell inoculation. Imaging studies: At screening, after monotherapy phase, before combination phase, and q9 weeks thereafter for 6 months, then q12 weeks. Patients who had PD but with clinical benefit may continue treatment. Subjects will continue to be followed for time on subsequent therapy (PFS2) and survival q3 mos. for 2 years. The phase 1 monotherapy part of the study has enrolled and treated 3 patients. Clinical trial information: NCT06471673 .

11515 Background: Chemotherapy agents cemcitabine, doxorubicin, and docetaxel have all demonstrated efficacy in soft tissue sarcomas (STS) but often result in significant toxicity. Therefore, we propose a combination chemo-immunotherapy regimen using metronomic low dose chemotherapy doses to reduce toxicity, with the addition of Nivolumab, a PD-1 inhibitor with demonstrated efficacy in STS. In this study, we aimed to determine the efficacy/safety of adding nivolumab to metronomic gemcitabine, doxorubicin, and docetaxel in subjects with advanced leiomyosarcoma (LMS) or liposarcoma (LPS). Methods: Objectives: Primary: To determine progression-free survival (PFS); Secondary: T evaluate the best overall response (BOR) and duration of response (DOR) by RECIST v1.1 via CT scan or MRI during the treatment period, determine progression-free survival rate (PFS) at 6 and 12 months and determine overall survival rate at 6 and 12 months Key eligibility criteria: ≥ 18 years, previously treated locally advanced unresectable or metastatic LMS/LPS, measurable disease by RECIST v1.1, acceptable hematologic and organ functions Treatment Schedule: Three-week treatment cycles with gemcitabine (600 mg/m2 max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Day 1 and Day 8, andnivolumab (240 mg) on Day 1 only. Results: Efficacy: The intention-to-treat population (n= 41), which includes patients who received at least one dose of gemcitabine, doxorubicin, and docetaxel, was used to determine the following: Median OS =16.1 months (95% CI: 7.4 to 20.1 months) and incidence of adverse events. The modified-intention-to-treat population (n= 31), which includes patients who completed at least the first 2 treatment cycles and follow-up CT/MRI, was used to determine the following: Median PFS = 8.6 (95% CI: 3.3-12.0) months; ORR = 22.6%; DCR = 87.5%; 6-month PFS rate = 58%; 6-month OS rate = 70.7%; 12-month PFS rate = 35.5%; 12-month OS rate = 59.1%; BOR = 7 PR, 21 SD, 4 PD. Safety: 28 of 41 patients (68%) experienced Grade 3/4 TRAEs that include: thrombocytopenia (n=12), lymphocyte count decreased (n=11), anemia (n=10), neutropenia (n=9), back pain (n=4), leukopenia (n=4), fatigue (n=2), dyspnea (n=2), hypocalcemia (n=1), muscle weakness (n=1), colitis (n=1), diarrhea (n=1), anorexia (n=1), abdominal pain (n=1), alkaline phosphatase increased (n=1), nausea (n=1), bone pain (n=1), peripheral sensory neuropathy (n=1), edema (n=1). There were no unexpected adverse events. Conclusions: Taken together, the results indicate that the combination regimen of nivolumab with metronomic gemcitabine, doxorubicin and docetaxel may have synergistic activity and is an effective treatment for advanced leiomyosarcoma and liposarcoma with manageable toxicity. Clinical trial information: NCT04535713 .