Search

4144 Background: Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. We reported last year the top-line clinical results of Phase I/IIa (PI/IIa) trial of STNM01, a synthetic RNA oligonucleotide to CHST15, as a second-line (2L) therapy in patients with progressive, unresectable pancreatic ductal adenocarcinoma (PDAC). Here we report the final PI/IIa results and follow-up clinical results investigating the changes of tumor microenvironmental parameters and the correlation with overall survival (OS). Methods: An additional clinical study was followed by PI/IIa trial (jRCT2031190055), which was a multicenter, open-label study of locoregional injections with STNM01 three times at 2 week-interval in 4 weeks as one cycle. A total of 3 cycles were repeated at maximum in combination with systemic 2L chemotherapy, oral fluoropyrimidine S-1 in the PI/IIa trial. The primary objective of this additional clinical study was OS. The secondary objectives were relations of tumor microenvironmental parameters evaluated by immunohistochemistry with OS. For comparison analyses, two-tailed unpaired t-test was performed. For correlation analyses, the Pearson coefficient analyses were performed. Results: A total of 22 patients were enrolled in the study. The average number of tumor-infiltrating CD3+ (13.8/mm2) and CD8+ T cells (8.0/mm2) at baseline in the evaluable population (n = 20) was at most one tenth or less, compared to historical data, indicating 2L population contained more T cell-immune suppressive patients. Baseline CD3+ and CD8+ T cells negatively correlated with tumoral CHST15 expression (p = 0.0051, p = 0.0478, respectively). As the final PI/IIa results, the median OS was 7.8 months with 6 and 12 months-survival rates of 68.2% and 31.8%, respectively. Disease control rate was 76.2% including 1 complete response. STNM01 led to a significant reduction in CHST15 at the end of cycle 1 compared to baseline (p = 0.0095, n = 19), and this was associated with increased CD3+ (p = 0.0331) and CD8+ T cells (p = 0.0146) and reduced CD33+ myeloid-derived suppressor cells (MDSCs) (p = 0.0281) in the tumor. Patient subpopulation who survived over 1 year (n = 5) showed a significant fold increase of CD3+ (p = 0.0033) and CD8+ T cells (p = 0.0147) and decrease of CD33+ MDSCs (p = 0.0403) at the end of cycle 1 compared to another subpopulation who survived less than 1 year (n = 13-14). Higher fold increase of CD3+ T cells (p = 0.0035, n = 19) or fold decrease of CD33+ MDSCs (p = 0.0212, n = 15) at the end of cycle 1 significantly correlated with longer OS. Conclusions: Locoregional injection of STNM01 was able to reactivate and augment tumor-infiltrating T cells while repress MDSCs. These changes in tumor immune cell profiles correlate with prolong prognosis in patients with first-line refractory, unresectable PDAC. Clinical trial information: jRCT2031190055.

103 Background: According to the National Comprehensive Cancer Network guideline, locally advanced rectal cancer is treated with chemotherapy with or without radiation, followed by transabdominal resection. However, there has been an emerging role for nonoperative management after chemoradiotherapy, and there is significant morbidity and risks associated with surgical resection. Endoscopic submucosal dissection (ESD) after chemoradiotherapy (CRT) for rectal cancer, which is termed “salvage ESD,” may be a viable option for patients, in terms of evaluating pathological response and providing potential curative resection. We aim to evaluate the feasibility and safety of salvage ESD. Methods: Retrospective chart review of cases of salvage ESD after CRT for locally advanced rectal cancer (salvage group) and standard ESD cases for rectal tumors without prior CRT (standard group) from July 2018 to August 2020 at our institution was performed. Clinical factors, imaging, procedural, and pathology results were collected and compared between the two groups. Results: 12 salvage ESD cases were compared to 27 standard ESD cases. 83.3% of the lesions in the salvage ESD group were initially staged as T3 prior to CRT. 100% of the lesions in the salvage ESD group were scarred down, compared to 33.3% in the standard ESD group (p

4120 Background: Carbohydrate sulfotransferase 15 (CHST15) is an enzyme that synthesizes heavily sulfated matrix glycosaminoglycan and shown to promote tumor invasion and correlate with poor prognosis in pancreatic ductal adenocarcinoma (PDAC). To explore the role of CHST15 blockage, we conducted a Phase I/IIa (P I/IIa) study to investigate the safety and efficacy of EUS guided locoregional injection of STNM01, a synthetic RNA oligonucleotide, in patients with unresectable PDAC, refractory to first-line chemotherapy. Methods: This was an open-label and dose-escalation study of STNM01 as second-line (2L) therapy in unresectable PDAC patients at 4 centers in Japan. One cycle consists of locoregional injection with STNM01 three times at 2 week-interval in 4 weeks (Days 0, 14 and 28 of dosing) in combination with systemic 2L chemotherapy. A 3+3 dose cohort escalation design initiated with 250 nM (n = 3) followed by 1,000 nM (n = 3), 2,500 nM (n = 3) and 10,000 nM (n = 4) was used for P I part. P IIa part (n = 9) was subsequently conducted with MTD or the highest dose level determined by P I. The primary outcome was incidence of DLT at the end of cycle 1. The secondary outcomes included overall survival (OS), local tumor response, histology and safety. This study was registered with jRCT (jRCT2031190055). Results: A total of 22 patients across 4 doses were enrolled in the study of which 21 were evaluable as per protocol population. All patients received S-1 as a systemic 2L chemotherapy and total 3 cycles were repeated at maximum. The most common AEs were abdominal pain and pyrexia. There were 9 grade 3 AEs. No drug-related SAE as well as DLT was observed. Since MTD was not reached in P I, P IIa was conducted with the highest dose, 10,000 nM. The 6-month survival rate in the entire population (n = 21) and in the highest dose population (n = 12; 3 for P I and 9 for P IIa) was 66.7 and 83.3%, respectively. In histological analyses, the % positive area of CHST15 tended to show dose-dependent suppression at the end of cycle 1, especially with 70.0% reduction from baseline in the highest dose population. Increased tumoral infiltrations of CD3+, CD8+ and CD20+ cells were observed during study period in the highest dose population. Local tumor response for the entire population showed 14 patients (66.7%) with stable disease. Notably, one patient showed complete disappearance on the CT image of both primary and metastatic tumors in the regional lymph node. Conclusions: Repeated locoregional injection of STNM01 is safe and well tolerated in patients with unresectable PDAC as combined 2L therapy. The 6-month survival rate of 10,000 nM of STNM01 was 83.3%, which is remarkable compared with previously reported data. Unexpected mode of action for tumoral lymphocyte infiltration also suggests the promising potential of locoregional injection of STNM01 as a new therapeutic option for PDAC. Clinical trial information: jRCT2031190055.

TPS262 Background: Definitive CRT is a standard-of-care for patients with medically inoperable esophageal cancer (EC, NEJM 326:1593). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that about ½ of patients have locally persistent disease (JAMA Oncol 3:1520). OBP-301 is a conditionally-restricted, replication-competent adenovirus derived from human adenovirus type 5 (Ad-5) that adds a human Telomerase Reverse Transcriptase (hTERT) gene promoter; it replicates only in tumor cells to cause lysis. It may enhance RT and may cause immunogenic cell death. A phase I study with RT in Japanese patients with inoperable EC showed tolerability and activity. Methods: In NRG-GI007, OBP-301 is added to weekly carboplatin/paclitaxel and RT to 50.4 Gy (1.8 Gy/fx ×28 fx) for patients with medically inoperable esophageal or gastroesophageal junction (GEJ) adenocarcinoma. Patients receive intratumoral OBP-301 1×1012 virus particles (vp)/ml via endoscopy (EGD) 3 days prior to CRT, then at days 12 and 26 of CRT, for a total of 3 doses. Restaging with PET and EGD occur 6-8 weeks later. Blood and tumor tissue are collected for immune- and viral-based correlative assays. Patients must be assessed to be medically inoperable and have ECOG performance status 2 of 6 patients have DLT, the dose of OBP-301 is reduced to 1×1011 vp/ml and another 6 patients will be treated. If 2 of 6 patients have DLT, then neither dose level will have met the safety rule and the trial will be ended. This trial opened to accrual on June 29, 2020. Clinicaltrials.gov NCT04391049. Funding: This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA180803 (IROC), from the National Cancer Institute (NCI) and Oncolys BioPharma. Clinical trial information: NCT04391049.

4568 Background: Pembrolizumab is approved for chemotherapy-refractory PD-L1 CPS >1 mEG cancer. In clinical trials, pts with MSI-H, EBV+ and PD-L1 CPS >10 EG cancers derive the greatest benefit with immune checkpoint blockade (ICB). Pre-clinical data suggest that the gut microbiome modulates response to ICB; however, the EG cancer microbiome has not been characterized in EG cancer with respect to PD-L1 and MSI-H status. Therefore, we evaluated the EG tumor microbiome in the context of PD-L1 expression in order to define biologically unique EG tumor phenotypes for future therapeutic development. Methods: Clinical and pathologic characteristics, including age, stage at diagnosis, tumor PD-L1 CPS, HER2 IHC, EBV ISH, genomic analysis, treatment history and survival status were reviewed. CPS was stratified a priori using cutoffs of >1/>10/>20 due to biologic differences. MSK-IMPACT, a capture-based next-generation sequencing platform that detects mutations, copy-number alterations, and select fusions was used to detect non-human bacterial reads identified in the NCBI NT database. Bacterial species found in >2 pts were analyzed and stratified by highest PD-L1 CPS score for each individual patient (Vanderbilt, AMP 2018) and Bonferroni correction was used for odds ratio (OR) confidence intervals where each unique species was considered an independent hypothesis. Results: Molecular data from 311 pts was clinically annotated. PD-L1 results (Table) correlated with bacterial species identified on tumor sequencing. PD-L1 CPS >1 was associated with Selenomonas sputigena (OR: 8.2, 95% CI:1.2-53.6), and PD-L1 CPS >20 was associated with presence of Bifidobacterium dentium (OR: 7.4, 95% CI:1.1-48.5) and Prevotella denticola (OR: 4.2, 95% CI: 1.1-16.6) after multiple comparison correction for the 166 bacterial species identified in the cohort. No differences were seen between PD-L1 < 10 vs >10. Four patients were also found to have EBV+ tumors using this approach, including the 1/54 patients identified by EBER ISH. Conclusions: PD-L1 > 20 EG cancer represents a biologically unique subset, enriched for Bifidobacterium dentium and Prevotella denticola. Correlation between PD-L1 expression, microbial and immune environment, and survival on ICB is underway. [Table: see text]

e22201 Background: Chondroitin sulfate E (CS-E) is known to promote tumor invasion by cleaving CD44 on pancreatic cancer cells. The biosynthesis of CS-E is mediated by specific enzyme carbohydrate ...