Lipase Increase Research Articles

Pembrolizumab for the First-Line Treatment of Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma: Results from the Single-Arm, Open-Label, Phase III KEYNOTE-913 Study.

The phase III KEYNOTE-913 study was conducted to evaluate the efficacy and safety of pembrolizumab as first-line therapy in patients with advanced Merkel cell carcinoma (MCC). The aim was to report results from the primary analysis of KEYNOTE-913. Patients with recurrent locally advanced or metastatic MCC received pembrolizumab 200mg intravenously every 3weeks for up to 35 treatments (~2 years). The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary end points were duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, overall survival (OS), and safety and tolerability. Fifty-five patients were treated with pembrolizumab. The median time from first dose to data cutoff (February 15, 2024) was 50.3 months (range 38.7-59.4). The ORR was 49% (95% confidence interval [CI] 35-63), with 12 complete responses and 15 partial responses. The median DOR was 39.8 months (range 4.8-52.5+), and the 24-month DOR rate was 69%. The median PFS was 9.3 months (95% CI 3-26), and the 24-month PFS rate was 39%. The median OS was 24.3 months (95% CI 12.4 to not reached), and the 24-month OS rate was 51%. Any-grade treatment-related adverse events (AEs) occurred in 38 patients (69%); 13 patients (24%) experienced grade 3-5 AEs. The most common treatment-related AEs were fatigue (n = 12 [22%]), pruritus (n = 12 [22%]), and lipase increase (n = 10 [18%]). One patient died of treatment-related Guillain-Barré syndrome. Pembrolizumab provided durable antitumor activity and promising survival and had a manageable safety profile in patients with recurrent locally advanced or metastatic MCC, supporting its use in this population. Clinicaltrials.gov, NCT03783078.

Brief Report: Phase II Trial of Regorafenib and Oral Methotrexate in Previously Treated Advanced KRAS-Mutant NSCLC

IntroductionThere are no standard targeted treatment options for advanced KRAS-mutant NSCLC beyond KRAS G12C inhibitors. A computational model identified regorafenib and low-dose methotrexate as synergistic in preclinical models of KRAS-mutant NSCLC. This study evaluated the efficacy and safety of the combination in previously treated advanced KRAS-mutant NSCLC. MethodsThis single-arm phase II study included regorafenib 80 to 120 mg daily and oral methotrexate dose escalated to tolerability from 10 to 20 mg twice weekly during the first cycle. Both agents were administered on weeks 1 to 3 of each 4-week cycle. The primary end point was progression-free survival. ResultsIn total, 18 patients with KRAS-mutant NSCLC were enrolled. Five patients received regorafenib at a 120 mg starting dose with four discontinuing due to toxicity; subsequently, 13 patients were treated at an 80 mg starting dose, with eight dose-escalating to 120 mg after the first cycle. Median progression-free survival was 3.7 months (95% confidence interval 1.8–8.6) and median overall survival was 10.4 months (95% confidence interval 5.2–30.3). The objective response rate was 16.7% and the 8-week disease control rate was 66.7%. Grade 3 treatment-related adverse events occurred in 11 patients, most often oral mucositis (n = 2) and asymptomatic lipase increase (n = 2). One patient developed asymptomatic grade 4 lipase increase. ConclusionsCombination treatment of regorafenib and oral methotrexate in patients with KRAS-mutant NSCLC was limited due to toxicity, and the study did not meet its primary end point. Computational modeling may aid in repurposing therapeutic options though caution must be exercised with tolerability.

A50-year-old patient with pancreatitis revealing pancreatitis, panniculitis, and polyarthritis syndrome-acase report and review of the literature.

The combination of pancreatitis, panniculitis, and polyarthritis (PPP) is arare systemic syndrome that occurs in patients with acute or chronic pancreatitis or pancreatic malignancies. A50-year-old male patient presented with polyarthritis increasing for 1week and consequent inability to walk unaided. In addition, the patient had several isolated nodules on the lower extremities without any tenderness to pressure. Laboratory tests showed elevated pancreatic enzymes indicative of pancreatitis, which was thereafter confirmed by abdominal CT scan, with signs of chronic pancreatitis and concrements in the pancreatic duct. The diagnosis of panniculitis was established by dermatological consultation. Considering all these clinical features, PPP syndrome was diagnosed. In accordance with the pre-existing literature, oral glucocorticoid therapy and nonsteroidal anti-inflammatory drugs (NSAIDs) were given but failed to improve pain and polyarthritis. In the further clinical course, due to the persistent increase in lipase and amylase, endoscopic retrograde cholangiopancreatography (ERCP) was performed, showing small concrements in the pancreatic duct. During the intervention, the pancreatic duct was widened, the small concrements were removed, and apancreatic duct stent was then implanted. Following ERCP, an instant decrease in pancreatic enzymes was observed, accompanied by aclear and sustained improvement of joint swellings and pain. With the typical triad of clinical findings in mind, one should consider PPP syndrome in the context of acute or chronic pancreatitis as well as in pancreatic malignancies. All involved disciplines (gastroenterology, dermatology, and rheumatology) should be familiar with this rare but severe condition. The prognosis depends on the extent of the functional deficit of the extremities and the progression of the underlying disease.

Alteration in oxidative stress markers, digestive physiology and gut microbiota of Heteropneustes fossilis and Clarias batrachus exposed to eriochrome black T

Synthetic dyes are the primary cause of water pollution in industrial regions. Azo dyes account for 60–70% of such dyes used in the textile sector due to their numerous beneficial characteristics. Nevertheless, there is a dearth of knowledge regarding the toxicity of Eriochrome Black T (EBT), a widely used azo dye in the textile industry. Therefore, the current study was designed to investigate the effect of EBT exposure on two catfish species, Heteropneustes fossilis and Clarias batrachus. Following 96 h exposure to 1, 10 and 20 mgL−1 of EBT, the MDA content and activities of SOD, CAT and GR exhibited a rising trend. However, as the concentration of EBT increased in both species, GPx showed decreased activity. EBT exposure also altered gut morphometry as well as the three main digestive enzymes activity (increase in lipase and trypsin activity, while decrease in amylase activity). In addition, the exposure of EBT had a significant impact on the gut microbiota of both species. C. batrachus demonstrated the suppression or absence of beneficial gut commensals (Bacillus and Cetobacterium), whereas H. fossilis revealed the proliferation and appearance of beneficial commensal microbes (Bacillus, Bacteroides, Prevotella, and Megashaera). Furthermore, the expansion or absence of these microbial communities indicated that the gut microbiota of both species was involved in dye digestion, immunity and detoxification. Overall, the percent change calculation of all the selected biomarkers, together with gut microbiota analysis, indicates that C. batrachus was more vulnerable to EBT exposure than H. fossilis. The present investigation effectively demonstrated the toxic impact of EBT on fish health by employing oxidative stress markers, digestive enzymes, and the fish gut microbiota as a promising tool for screening the impact of dye exposure on digestive physiology in toxicological research.

Embolization of the Pancreas Using Microspheres: A Proof-of-Safety Study in a Porcine Model

PurposeTo evaluate safety and impact of particle embolization on pancreatic function in a pig model. Materials and MethodsEmbolization of the dorsal pancreatic artery using 100–300-μm particles was performed on 14 Yorkshire pigs. Baseline and post-embolization glucose tolerance testing results and serum amylase/lipase levels were obtained. Pigs were observed for 2 weeks to assess for behavioral signs of pain/distress, bowel changes, and changes to intake/output. After 2 weeks, euthanasia and necropsy with gross and histopathologic assessment of the pancreas were performed. ResultsEmbolization was technically successful in all pigs. All animals survived the 2-week follow-up without evidence of pain/distress. There were significant increases in amylase and lipase at 24 and 48 hours (P < .001), which normalized by 2 weeks. There was minimal change in glucose tolerance testing at 2 weeks. Bowel habits were unchanged without diarrhea. At necropsy, all examined pancreases had fibrosis in the distal body and tail, without gross evidence of ongoing inflammation. On histopathologic evaluation, all pancreases demonstrated fibrosis in the embolized portions without evidence of active inflammation in treated or adjacent pancreatic tissue. ConclusionsParticle embolization of the pancreas was feasible and tolerated by all tested pigs with transient amylasemia, lipasemia, and mildly impaired glucose tolerance but without clinical or histopathologic evidence of acute pancreatitis and no evident impact on pancreatic endocrine or exocrine function.

Outstanding safety and efficacy data of IMC002, an autologous CLDN18.2-targeting CAR-T, in CLDN18.2+ advanced solid tumors.

e16012 Background: Claudin 18.2 (CLDN18.2) is a promising therapeutic target for advanced solid tumors with CLDN18.2 expression. IMC002 is an autologous CLDN18.2-targeting CAR-T cell directed by a CLDN18.2-specific VHH, the specificity of which was confirmed by a membrane proteome array assay. Preclinical studies showed that IMC002 exhibited high tumor specificity, anti-tumor efficacy, and excellent safety profile in both cell and animal models. Methods: This is an open label first in human Phase 1 dose escalation study to evaluate the safety and efficacy of IMC002 in advanced solid tumors with CLDN18.2 expression which is defined as CLDN18.2 expression of ≥1+ membrane staining intensity in ≥10% tumor cells. Accelerated titration followed by Bayesian optimal interval design was adopted with a total of 4 dose levels planned at 1, 3, 5 and 7 million (mil) CAR-T cells/kg respectively. All patients (pts) were given a single dose of IMC002 infusion after lymphodepletion chemotherapy. Dose limiting toxicity (DLT) was evaluated during the 28-day period after IMC002 infusion. Safety, anti-tumor activity, pharmacokinetics and pharmacodynamics were explored in this study. Here, we present preliminary safety and efficacy data for the pts dosed with up to 3 mil CAR-T cells/kg. Results: As of January 17, 2024, 3 advanced unresectable gastric cancer pts received IMC002 infusion, 1 patient at 1 mil CAR-T cells/kg and 2 pts at 3 mil CAR-T cells/kg. No DLT or SAE was reported. Manageable CRS (grade 1) was reported in all 3 pts. Other adverse events related to cell therapy included grade 1-2 lipase increase (3/3), diarrhea (1/3), pruritis (1/3) and γ-GGT increase (1/3). All adverse events recovered quickly. Preliminary efficacy data showed that best overall response of the 3 pts was all stable disease as evaluated by RECIST 1.1. The two pts at the dose level of 3 mil CAR-T cells/kg underwent successful radical surgery at week (W) 11 and 44 after IMC002 infusion respectively. Pathological complete response (pCR) was achieved in the patient with surgery at W44. Distinct CAR-T cell expansion in peripheral blood was observed in all 3 pts, with the peak number of CAR+ cells reaching on day 7-11 in the peripheral blood after the infusion. Moreover, CAR-T cell infiltration was detected in the W11 and W44 surgical samples. Significant elevations of serum levels of IFN-γ, IL-10, IP-10, IL-2 and IL-6 were observed in the 3 pts. The trial is ongoing. Conclusions: IMC002 showed a favorable safety profile, encouraging anti-tumor activities with observed pCR and persistent expansion in the tumor tissue at the low dosage levels in pts with advanced CLDN18.2+ gastric cancer. In addition, our trial has successfully provided a surgical treatment opportunity after CAR-T therapy downstaging of unresectable gastric cancers. Clinical trial information: NCT05472857 .

A randomized, controlled, phase 2 trial of nivolumab plus standard-dose or low-dose bevacizumab for recurrent glioblastoma (NAVAL).

2072 Background: PD-1/PD-L1 inhibition has demonstrated limited efficacy for recurrent glioblastoma (rGBM) across prior RCTs. VEGF, a proangiogenic factor upregulated in rGBM, contributes to tumor-associated immunosuppression. Preclinical and observational clinical data indicate a potential dose-dependent effect of anti-VEGF therapy on immune response. This RCT evaluated anti-PD-1 plus anti-VEGF therapy for rGBM. Methods: NAVAL was a multicenter, open label, phase 2 RCT that enrolled 90 patients (≥18 years) with GBM at first recurrence. Participants received nivolumab (240 mg IV Q2 weeks), and were 1:1 randomized to concurrent 10 mg/kg bevacizumab ( standard-dose arm) or 3 mg/kg bevacizumab ( low-dose arm) administered IV biweekly. Stratification factors included age, performance status, extent of resection, and MGMT methylation status. Primary endpoint was overall survival (OS) at 12 months (OS-12). Other outcomes were overall objective response rate (ORR), median progression-free survival (PFS), PFS at 6 months (PFS-6), and safety. Exploratory genomic and immune profiling using CITEseq was performed in 16 patients. Results: 90 patients were enrolled with median age of 60.6 years (range 27-86). 35 patients were MGMT methylated, 53 were unmethylated and 2 were indeterminate. Final analysis had 87 evaluable patients, with median follow-up of 146 days (range 7-1239). There were 3 complete responses (3.4%), 29 partial responses (33.3%), 37 stable disease (42.5%), and 18 progressive disease (20.7%). OS-12 was 41.1% and 37.7% in standard-dose and low-dose arms respectively, with PFS and ORR data in table. Post-hoc analysis demonstrated survival benefit for patients aged ≥60 years in standard-dose arm. Most frequent toxicities (&gt;20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Grade 3-4 toxicities included hypertension (7.8%), fatigue (5.6) and non-neurological toxicities. Differential changes across trial arms were seen in myeloid-derived suppressor cells (MDSCs) post-therapy. Network medicine identified VEGF as target to reduce MDSCs. VEGF was found expressed by MDSCs of mainly responder patients. Differential gene expression analysis identified increased pro-inflammatory gene signatures in standard-dose arm. Conclusions: Overall PFS and OS were similar for nivolumab plus standard- or low-dose bevacizumab for rGBM, with post-hoc survival benefit seen in standard-dose arm in elderly. Standard-dose bevacizumab was associated with increased systemic inflammatory response and reduced immunosuppressive MDSCs. Clinical trial information: NCT03452579 . [Table: see text]

Abstract PO3-05-12: Randomized Phase 2 of Bria-IMT, an Allogenic Human Cell Line with Antigen Presenting Activity, in Heavily Pretreated Metastatic Breast Cancer

Abstract Introduction Despite progress in MBC, too many continue to succumb due to treatment resistance or intolerance. SV-BR-1-GM is an allogenic human breast cancer cell line with antigen presenting cell activity designed to overcome the immune-suppressive tumor microenvironment while being acceptable to extensively pretreated contemporary MBC patients. We report interim exploratory analysis of the ongoing RCT of the Bria-IMT regimens. Methods An interim exploratory analysis using preliminary partially available evaluable data of the ongoing prospective, randomized phase 2 (NCT03328026; 2018-present) of Bria-IMT (irradiated SV-BR-1-GM) with a PD-1check point inhibitor (CPI) every 3 weeks (25 patients dosed to date). Both regimens include cyclophosphamide 300 mg/m2 48-72 hours prior to intradermal Bria-IMT (~20 x 106 cells) followed by interferon-alpha at the inoculation sites 2 days later. The control arm used the original sequence with simultaneous start of Bria-IMT and CPI in cycle 1. The experimental arm started CPI in cycle 2 after the 2nd inoculation. Candida skin test was performed before cycle 1 to determine anergy status while delayed-type hypersensitivity skin test (DTH), defined as &amp;gt;5mm erythema &amp; induration, was done at every cycle by intradermal injection of a small test dose of Bria-IMT prior to full dose inoculation. Results Median age: 58 (range 37-81); median prior therapies: 8 lines (range 4-18); 89% were grade 2/3 (n=18); 68% hormone receptor positive; 61% HER2 negative, 33% HER2 low, and 6% HER2 high; 33% triple negative. Overall, 53% of subjects had a clinical benefit as best response by BICR, PI or target lesion measurement. The two treatment arms were similar with a trend showing longer median durations on therapy (mDOT) of 3.7 mo in the experimental delayed CPI arm compared with mDOT = 2.9 for original sequence control arm. 47% of patients were anergic to candida. Among all anergic subjects, the mDOT was 3.5 compared to 2.5 mo for non-anergic patients. However, among anergic subjects, the alternative treatment arm had a lower risk of treatment discontinuation (improved HR) with mDOT of 3.7 compared to the 3.3 mo mDOT of the original treatment. 50% of anergic subjects eventually developed DTH to SV-BR-1-GM. mDOT was 4.0 mo for DTH+ pts vs 3.0 mo for those who did not mount DTH. Median OS was not yet reached; mean OS was higher in non-anergic vs anergic pts. Among those who developed an inoculation site reaction to Bria-IMT, OS was greater than for those who did not. Time on the Bria-IMT regimen exceeded the time on penultimate treatment in 22% of subjects while 33% of subjects with prior CPI use exceeded last therapy. AEs were mild with 28% of subjects (n=7) having &amp;gt; grade 3 events. The most common grade 3+ AE was lipase increase (n=3). One subject with encouraging changes in peripheral blood tumor markers and CTCs completed a PET study using Zr-89 crefmirlimab berdoxam, a zirconium-89 labelled truncated antibody specific to human CD8α (CD8 Immuno-PET) and demonstrated increased uptake in some metastatic lesions and draining lymph nodes. Updated results will be provided at the meeting. Conclusion Sequencing of CPI with Bria-IMT is associated with differential clinical outcome trends but not statistically significant in this interim preliminary exploratory analysis regardless of prior CPI use. Bria-IMT is immunogenic with clinical benefit demonstrated for both treatment schedules among patients with inducible DTH reactions. Patients who develop an immune response to Bria-IMT had an increase in OS compared to those who did not. The nodal localization of CD8+ cells on PET may indicate a systemic activation of CD8 positive lymphoid cells. It also provides support that the Bria-IMT + CPI combination immune-based therapy can result in an increase of CD8+ tumor infiltrating lymphocytes in breast cancer metastatic sites. These preliminary results will be evaluated in the ongoing randomized phase 3 pivotal registrational trial. Citation Format: Carmen Calfa, Chaitali Nangia, Minal Barve, John Knecht, Jarrod Holmes, Kendrith Roland, Ralph Boccia, Frances Valdes-Albini, Zach Gostout, Mingjin Chang, William Williams, Charles Wiseman, Bonnie Guerin, Shaker Dakhil, Giuseppe Del Priore, Saranya Chumsri. Randomized Phase 2 of Bria-IMT, an Allogenic Human Cell Line with Antigen Presenting Activity, in Heavily Pretreated Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-12.

Abstract CT133: A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer

Abstract Background: TIM3 is an inhibitory immunoreceptor linked to decreased activity of immune cells in the tumor microenvironment. S095018 is a human anti-TIM3 IgG2 antibody which blocks binding of phosphatidyl serine to TIM3 promoting the stimulation of T-cells, dendritic cells (DCs) and macrophages. Sym021 is a humanized IgG1 antibody that inhibits binding of PD-1 with its ligands PD-L1 and PD-L2. Preclinical data demonstrated that Sym021 combined with S095018 results in enhanced immunostimulatory antitumor activity. Methods: S095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancer whose disease progressed under treatment with at least one line of systemic therapy and who had not received prior treatment with PD-1/-L1 inhibitors (NCT04641871). The dose/schedule of Sym021 and S095018 was 3mg/kg IV Q2W and 10mg/kg IV Q2W, respectively. Primary endpoints included overall response rate (ORR) using RECIST v1.1 and incidence/severity of adverse events. Key secondary endpoints included PK parameters, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results As of 31-Oct-2023, 35 patients with stage IV biliary tract cancer (34 cholangiocarcinoma, 1 gallbladder adenocarcinoma) received S095018 in combination with Sym021. All patients were naïve to prior immune checkpoint inhibitor treatment. Twenty-two patients (62.9%) had received 1 prior antineoplastic systemic treatment for advanced/metastatic disease, 34.3% had received ≥2 prior treatments for advanced/metastatic disease. Overall, 34 patients (97.1%) discontinued treatment, 85.7% due to disease progression. Best overall response was 2 PR (5.7%), 11 SD (31.4%), 18 PD (51.4%) and 4 not evaluable. Median PFS and OS were 1.9 months (90% CI 1.8-3.7) and 13.4 months (90% CI 8.2-27.1) respectively. Disease control rate (CR+PR+SD) with SD≥16 weeks, ≥24 weeks and ≥12 months was 28.6%, 22.9% and 8.6% respectively. Treatment emergent adverse events of any grade occurring in &amp;gt;5% of patients included fatigue, pruritus, alkaline phosphatase increase, amylase increase, IRR (each 8.6%) and hypothyroidism, hyperthyroidism, AST increase, lipase increase and myalgia (each 5.7%). Exploratory biomarker analyses in paired tumor biopsies (N=18) showed an intratumoral increase in CD8 T-cell density, as well as upregulation of gene signatures related to IFNg signaling, antigen presentation, T-cell activation and cytotoxicity upon treatment. Baseline tumor biopsies from the two patients who achieved confirmed PR showed high PD-L1 expression. Conclusions: S095018 in combination with Sym021 exhibited antitumor activity in patients with advanced/metastatic recurrent biliary tract cancer who had not received prior treatment with PD-1/-L1 inhibitors. The combination was well tolerated without new safety signals. Further biomarker analysis is ongoing. Citation Format: Francois Ghiringhelli, Richard Kim, Teresa Macarulla, Irene Moreno, Albiruni Razak, Jordi Rodon, Chih-Yi Liao, Thomas Marron, Judith Raimbourg, Helene Kaplon, Julia Geromini, Najah Harouki, Christelle Rodrigues, Pauline Darcel, Niels Jorgen Skartved, Rikke Hald, Daleen Lopez-Ravnborg, Peng He, Xenophon Ianopoulos, Vasileios Askoxylakis, Nehal J. Lakhani, Sarah Davis, Amit Mahipal. A phase 1b multicenter study of anti-TIM3 (S095018/Sym023) in combination with anti-PD1 (Sym021) in patients with advanced/metastatic recurrent biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT133.

Abstract CT192: A first-in-human phase 1 study of TQB2916, a novel CD40 agonist antibody for advanced malignancies

Abstract Background: CD40 receptor is a member of the tumor necrosis factor receptor family that plays a prominent role in immune responses. TQB2916, a humanized IgG2 CD40 monoclonal antibody, has demonstrated CD40 agonistic activity and promising anti-tumor activity in preclinical studies. A first-in-human study of TQB2916 single agent in advanced solid tumors and lymphomas is ongoing (NCT05213767). Methods: Patients with an ECOG performance status of 0 or 1, adequate hematologic and organ function and refractory to standard therapies met inclusion criteria. TQB2916 was given intravenously every 3 weeks until progression or unacceptable toxicity. Bayesian optimal interval (BOIN) design was used to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). The objective is to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of TQB2916. Results: From April 2022 to November 2023, 18 patients with solid tumors and 2 with lymphoma have been treated with TQB2916 monotherapy, and were assigned to 7 cohorts (0.5 mg n=1, 2.5 mg n=1, 12.5 mg n=3, 60 mg n=3, 200 mg n=7, 300 mg n=2, and 400 mg n=3). Three dose limiting toxicities (DLTs) were observed: one with grade 3 pneumonia and one with grade 4 lipase/amylase increase in the 400 mg cohort; one with grade 3 pancreatitis in the 300 mg cohort. All patients experienced at least one treatment-related adverse event (TRAE). The most common TRAEs were lipase increase (n=15, 75%), amylase increase (n=14, 70%), lymphocyte count decrease (n=13, 65%), alanine aminotransferase (ALT) increase (n=12, 60%), alkaline phosphatase (ALP) increase (n=12, 60%), aspartate aminotransferase (AST) increase (n=11, 55%), hypoalbuminemia (n=11, 55%), and anorexia (n=11, 55%). Serious TRAEs occurred in 5 (25%) patients. Most of TRAEs were of grade 1 or grade 2 and manageable. Sixteen patients were evaluated for efficacy, and 3 of them achieved stable disease as per immune response evaluation criteria in solid tumors (iRECIST) and lymphoma response to immunomodulatory therapy criteria (LYRIC). The pharmacokinetics were well-behaved with increasing exposure dose-proportionally and no accumulation occurred after repeated dosing. The Cmax, AUC(0-t) and T1/2 of 400 mg single dosing were 109±21.8 μg/ml, 611±228 d*µg/mL and 5.54±3.37 d. Dose-dependent occupancy of CD40 was detected of 0.5 mg and above doses. Reduction in peripheral B cells and increasing in cytokines secretion were also observed. Conclusions: Pharmacodynamics analysis suggested that TQB2916 treatment achieved CD40 occupancy and immune activation with the changes in cytokines. Considering the safety profile and efficacy, 200 mg was determined as the preliminary expansion dose as it was well tolerated. Studies of TQB2916 in combination with immune checkpoint inhibitors and/or other anti-cancer therapies are ongoing. Citation Format: Yi Ba, Huilai Zhang, Ting Deng, Tao Ning, Qian Fan. A first-in-human phase 1 study of TQB2916, a novel CD40 agonist antibody for advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT192.

Abstract CT035: Proof-of-concept and preliminary efficacy of triple IAP blockade to maximize immunogenic cell death and induce efficient adaptive immune response: First report on the ASTEROID phase 1 trial

Abstract Background: Dying cells play an important role in CD8+ T cell-mediated immunity. While apoptosis is mainly immunologically silent, necroptosis is immunogenic and can more efficiently initiate an adaptive immune response that could be augmented by immune checkpoint inhibition (ICI). Inhibitor of Apoptosis (IAP) proteins are key gatekeepers of how a cell dies, and frequently overexpressed in cancer. ASTX660 (tolinapant) is a triple blocker of cIAP1/2 and XIAP, sensitizing cancer cells to death ligands through ripoptosome formation, activating ‘danger’ co-stimulatory signals and dendritic cell (DC) maturation required to prime a potent antitumor response. Methods: We assessed the safety, pharmacodynamic (PD), and clinical activity of 7 days of oral ASTX660 given prior to pembrolizumab 200 mg (Q3W), in patients (pts) refractory to standard therapy. TITE-CRM was used to explore ASTX660 doses 90-180 mg. Serial paired blood and tumor samples were analyzed to interrogate the effect of ASTX660 on cell death, tumor microenvironment and host immune system. Results: 22 pts have been enrolled; median age 55 years (range 38-81); male:female 5:17; all ECOG PS ≤1; median 4.5 prior therapies. Tumor types included breast, head and neck (HN), hepatocellular, cervical, pancreatic and cholangiocarcinoma. Combination ASTX660-pembrolizumab is currently recruiting at highest dose 180 mg without any dose limiting toxicities (DLT) seen within the 6-week DLT observation period. Most common adverse events (AE) were G1-2 rash, nausea, and asymptomatic increases in amylase, lipase and transaminases; all reversible and easily manageable. Four iRECIST confirmed partial responses were seen in 10 efficacy evaluable pts treated at biologically active dose levels 120 and 150 mg (Overall response rate 40%), including 2 pts with ER+ HER2- breast cancer, 1 cervical adenocarcinoma pt (exceptional response following initial pseudoprogression) and a HN cancer pt refractory to ICI monotherapy. 3/4 responders are ongoing. Efficacy data from pts treated at highest dose level 180 mg is pending. FACS of paired blood samples from responders shows a significant rise in %CD57+/CD3+ cytotoxic effector T cells [mean 11.90% (pre-) vs 14.25% (post-ASTX660); p=.0176]. These changes were not seen in the non-responders group. Full PD from paired blood and tumour sampling will be shared at the meeting. Conclusion: ASTX660-pembrolizumab is is well-tolerated with durable antitumor responses in pts with immunologically cold tumors, providing the first clinical proof-of-concept of immunogenic cell death induction leading to effective adaptive immune response when combined with ICI. Recommended Phase 2 dose optimization and expansion cohorts in immunologically cold cancers are ongoing. Citation Format: Crescens Tiu, Wing Yau, Victoria Sanchez-Perez, Giovanni Codacci-Pisanelli, Ching Leung, Eden S. Andrews, Bristi Basu, Anna Zachariou, Toby Prout, Mona Parmar, Alison Turner, Xiaoran Lai, Zhulin Yin, Karen E. Swales, Syed Haider, Thomas Lund, Diego C. Dos Reis, Tatiany L. Silveira, Alan S. Dunlop, Ann-Marie Baker, Bora Gurel, Ana Ferreira, Claudia Bertan, Nina Tunariu, Edward W. Johnston, Alistair Ring, Tencho Tenev, Tomoko Smyth, Simone Jueliger, Udai Banerji, Johann S. de Bono, Alec Paschalis, Adam Sharp, Anna Minchom, Christina Yap, Pascal Meier, Juanita S. Lopez. Proof-of-concept and preliminary efficacy of triple IAP blockade to maximize immunogenic cell death and induce efficient adaptive immune response: First report on the ASTEROID phase 1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT035.

New insights into the effect of xylooligosaccharide derived from agricultural waste, single or combined dietary supplementation with mixed probiotics on growth, flesh quality, health condition and disease resistance in Nile tilapia (Oreochromis niloticus)

This study aimed to study the effects of single or combined dietary supplementation of xylooligosacharides (XOs), prebiotics derived from agricultural waste and mixed probiotics (Bacillus subtilis TISTR 008 and Lactobacillus plantarum TISTR 1854) on growth performance, flesh quality, health condition and disease resistance in Nile tilapia (Oreochromis niloticus). Fish received four types of diets: a basal diet (control); XOs (prebiotics); a mixture of Bacillus subtilis TISTR 008 and Lactobacillus plantarum TISTR 1854 (probiotics); and a combination of XOs and a probiotic mixture (synbiotics) for 56 days. The results show that dietary prebiotics, probiotics, and synbiotics improved growth performance including final body weight, weight gain, average daily gain, and protein efficiency ratio compared to the control diet. Interestingly, the feed conversion ratio was improved by dietary prebiotics, probiotics, and synbiotics supplementation. Concurrently, innate immunity parameters such as total antioxidant, lysozyme, catalase, and glutathione S transferase were mostly higher in fish fed the prebiotics, probiotics, and synbiotics diets. Moreover, we observed significant increases in digestive enzyme activities, including protease, amylase, and lipase, in fish fed probiotic diets. After the feeding trial, fish were intraperitoneally injected with Streptococcus agalactiae, and the cumulative 14-day mortality rate was calculated. High survival rates were observed in all groups that received supplementation with prebiotics, probiotics, or synbiotics in their feed. This improvement is correlated with an increase in the transcriptional levels of immune- and growth-related factors. Interestingly, this study highlights the use of prebiotics and synbiotics containing XOs to boost the PUFA n-3 and n-6 content in the fish fillets. Our findings indicate that adding XOs as prebiotics to the diet significantly enhances the overall performance of fish when compared to the effects of probiotics and synbiotics. In summary, XOs may have the potential as organic compounds derived from agricultural waste for specific probiotic and synbiotic products in the aquaculture industry when combined in the right proportions.

HIV and gp120-induced lipid droplets loss in hepatic stellate cells contribute to profibrotic profile

Liver fibrosis is the excessive accumulation of extracellular matrix proteins, primarily collagen, in response to liver injury caused by chronic liver diseases. HIV infection accelerates the progression of liver fibrosis in patients co-infected with HCV or HBV compared to those who are only mono-infected. The early event in the progression of liver fibrosis involves the activation of hepatic stellate cells (HSCs), which entails the loss of lipid droplets (LD) to fuel the production of extracellular matrix components crucial for liver tissue healing. Thus, we are examining the mechanism by which HIV stimulates the progression of liver fibrosis. HIV-R5 tropic infection was unable to induce the expression of TGF-β, collagen deposition, α-smooth muscle actin (α-SMA), and cellular proliferation. However, this infection induced the secretion of the profibrogenic cytokine IL-6 and the loss of LD. This process involved the participation of peroxisome proliferator-activated receptor (PPAR)-α and an increase in lysosomal acid lipase (LAL), along with the involvement of Microtubule-associated protein 1 A/1B-light chain 3 (LC3), strongly suggesting that LD loss could occur through acid lipolysis. These phenomena were mimicked by the gp120 protein from the R5 tropic strain of HIV. Preincubation of HSCs with the CCR5 receptor antagonist, TAK-779, blocked gp120 activity. Additionally, experiments performed with pseudotyped-HIV revealed that HIV replication could also contribute to LD loss. These results demonstrate that the cross-talk between HSCs and HIV involves a series of interactions that help explain some of the mechanisms involved in the exacerbation of liver damage observed in co-infected individuals.

Fever-like temperature impacts on Staphylococcus aureus and Pseudomonas aeruginosa interaction, physiology, and virulence both in vitro and in vivo

BackgroundStaphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) cause a wide variety of bacterial infections and coinfections, showing a complex interaction that involves the production of different metabolites and metabolic changes. Temperature is a key factor for bacterial survival and virulence and within the host, bacteria could be exposed to an increment in temperature during fever development. We analyzed the previously unexplored effect of fever-like temperatures (39 °C) on S. aureus USA300 and P. aeruginosa PAO1 microaerobic mono- and co-cultures compared with 37 °C, by using RNAseq and physiological assays including in vivo experiments.ResultsIn general terms both temperature and co-culturing had a strong impact on both PA and SA with the exception of the temperature response of monocultured PA. We studied metabolic and virulence changes in both species. Altered metabolic features at 39 °C included arginine biosynthesis and the periplasmic glucose oxidation in S. aureus and P. aeruginosa monocultures respectively. When PA co-cultures were exposed at 39 °C, they upregulated ethanol oxidation-related genes along with an increment in organic acid accumulation. Regarding virulence factors, monocultured SA showed an increase in the mRNA expression of the agr operon and hld, pmsα, and pmsβ genes at 39 °C. Supported by mRNA data, we performed physiological experiments and detected and increment in hemolysis, staphyloxantin production, and a decrease in biofilm formation at 39 °C. On the side of PA monocultures, we observed an increase in extracellular lipase and protease and biofilm formation at 39 °C along with a decrease in the motility in correlation with changes observed at mRNA abundance. Additionally, we assessed host–pathogen interaction both in vitro and in vivo. S. aureus monocultured at 39οC showed a decrease in cellular invasion and an increase in IL-8—but not in IL-6—production by A549 cell line. PA also decreased its cellular invasion when monocultured at 39 °C and did not induce any change in IL-8 or IL-6 production. PA strongly increased cellular invasion when co-cultured at 37 and 39 °C. Finally, we observed increased lethality in mice intranasally inoculated with S. aureus monocultures pre-incubated at 39 °C and even higher levels when inoculated with co-cultures. The bacterial burden for P. aeruginosa was higher in liver when the mice were infected with co-cultures previously incubated at 39 °C comparing with 37 °C.ConclusionsOur results highlight a relevant change in the virulence of bacterial opportunistic pathogens exposed to fever-like temperatures in presence of competitors, opening new questions related to bacteria-bacteria and host–pathogen interactions and coevolution.

Validity of Predictive Markers for Post ERCP Pancreatitis Patients: A Single Centre Study

Abstract: Endoscopic retrograde cholangiopancreatography (ERCP) is a proprietary procedure, endoscopic modality, and specialized procedure used to diagnose and treat disorders of the pancreatic and biliary systems. The incidence of reported post-ERCP complications varied among several studies including post ERCP pancreatitis (PEP), duodenal perforation, and cholangitis. In this study, the author would like to show certain intra procedural factors related to PEP incidence. This was a retrospective study of secondary data of patients undergoing ERCP procedures from 2017-2022 at Prof. Dr. R. D. Kandou Hospital, Manado. Length of procedure, cannulation on pancreatic duct, pancreatogram, double wire technique, and the use of certain common bile duct (CBD) stone retrieval techniques such as endoscopic papillary balloon dilatation (EPBD) were recorded and analyzed. The results showed that based on the analyzed data, the percentage of pancreas cannulation was 8%, pancreatogram 5%, double-wire technique 3%, and EPBD procedure 10%, Incidence rate of PEP in all ERCP procedures was 19%. Increased amylase/lipase enzymes were found in 13 of 24 patients (54%) who underwent cannulation; 8 of 16 patients (50%) who underwent pancreatogram; 4 of 9 patients (44%) who underwent double wire procedure; and 10 of 30 patients (33%) who underwent EPBD. This PEP could be caused by several risk factors during ERCP including cannulation, pancreatogram, double wire, and EPBD. Number of cannulation attempt could result in trauma to the ampulla. Pancreatogram could result in hydrostatic, chemical, and allergic injury. Any manipulation of the pancreas that caused trauma could trigger the incidence of PEP. Assessment of the occurrence of PEP was based on increases in lipase and amylase enzyme values by four times the normal value and tested 6 hours after procedure. We could reduce the incidence of PEP by providing prophylactic therapy before ERCP. In conclusion, PEP is the most common complication in ERCP procedures and can be risky in patients with high risk factors. In this study, factors that affecting the incidence of PEP are cannulation, pancreatogram, double wire and EPBD. Keywords: endoscopic retrograde cholangiopancreatography; pancreatitis; complications

Results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody) in combo with pembrolizumab (Pembro) in patients (Pts) with metastatic microsatellite-stable (MSS) colorectal cancer (CRC).

127 Background: ADG126 is a fully human anti-CTLA-4 IgG1 SAFEbody that has a cleavable masking peptide that blocks the antigen binding site. ADG126 is preferentially activated in the tumor microenvironment to afford prolonged on-tumor drug exposure and limited off-tumor toxicity. Activated ADG126 binds to a unique CTLA-4 epitope to prime T cells via partial ligand blockade and deplete immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC)/phagocytosis (ADPC). Preclinical studies showed that ADG126/Pembro combination effectively increases Teff/Treg ratio. In Phase 1b/2 studies, ADG126 demonstrated a favorable safety profile and clinical efficacy as monotherapy and in combination with anti-PD-1 therapy. Here we present results of the entire dose escalation and ongoing dose expansion cohorts including a cohort of patients with MSS CRC free of liver metastasis (NCT05405595). Methods: This is a Phase 1b/2, open-label, multicenter dose escalation and expansion study of ADG126/Pembro. Pts received ADG126 [6 or 10 mg/kg (mpk), Q3W or Q6W, IV] plus Pembro (200 mg, Q3W, IV). Primary endpoints are safety and tolerability. Secondary endpoints are PK, ADA, ORR, DCR, DOR and PFS per RECIST 1.1. Results: As of Aug 29, 2023, a total of 47 Pts have been treated in dose escalation (N=11) and expansion cohorts (N=36). The median age is 60.5 yrs (26-78); 31.9% Pts had at least 3 prior therapies, 12.8% Pts received prior IO therapies. A majority of Pts (74.5%) have what are considered immunologically “cold” tumors. ADG126 was dosed at 6 mpk Q6W (1 Pt) and Q3W (5 Pts), 10 mpk Q6W (17 Pts) and Q3W (24 Pts), and Pembro was dosed at 200 mg Q3W. No DLT or Grade 4/5 TRAE was observed at any dose level. TRAEs more than 10% are pruritis (N=9, 19.1%) and diarrhea (N=5, 10.6%). Grade 3 TRAEs were observed in 5 subjects: 1 G3 diarrhea (6 mpk, 16.7%), 1 G3 adrenal insufficiency (10 mpk Q6W, 5.9%), 1 each G3 pancreatitis, blurred vision and lipase increase (10 mpk Q3W, 12.5%); all TRAEs occurred after repeat dosing. For the MSS CRC expansion cohort, 7 SDs at ADG126 10 mpk Q6W dose level (N=11) were observed, and 2 PRs (including 1 initial PR) and 4 SDs at 10 mpk Q3W (N=13) were observed. Conclusions: ADG126/Pembro combination is well-tolerated up to the maximally administered dose of 10 mpk Q3W, with limited G3 TRAEs comparable to Pembro monotherapy. The 10 mpk ADG126 Q3W repeat dosing regimen maintains a favorable safety profile and demonstrates anti-tumor activity. The MSS CRC cohort of 10 mpk ADG126 Q3W surpassed the threshold set for part 1 of the Simon’s 2-stage design, and the second stage of the cohort is now enrolling. In conclusion, ADG126/Pembro has a significantly improved therapeutic index over the same class agents in combination with anti-PD-1 therapy, and encouraging early outcomes in patients of MSS CRC without liver metastasis. Clinical trial information: NCT05405595 .

R-GemOx Plus Nivolumab Vs R-GemOx As Second-Line Therapy for Large B-Cell Lymphoma in Transplant-Ineligible Patients: Interim Analysis of the Niveau Trial, an International, Randomized Phase 3 Study of the AGMT, GLA, HOVON, Lysa and PLRG

Introduction: Patients (pts) with relapsed or refractory ( R/ R) large B-cell lymphoma (LBCL) after first-line treatment who are unable to undergo consolidative high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) have poor outcomes and limited treatment options. Rituximab, gemcitabine and oxaliplatin (R-GemOx) is a common immuno-chemotherapy regimen used in this setting. The objective of the open-label, phase 3, NIVEAU study (NCT03366272) was to evaluate the efficacy and safety of Nivolumab added to R-GemOx in pts with R/ R LBCL after 1 prior line of therapy not eligible for HDCT/HSCT owing to age and/or comorbidities. Patients and Methods: Eligible pts were adults with R/R LBCL that were refractory to or had relapsed after first-line immuno-chemotherapy and who were not deemed candidates for HDCT/HSCT based on physician's assessment and at least one of the following criteria: age ≥65 years; age ≥18 years and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score ≥3; or age ≥18 years and prior ASCT (as 1st line consolidation). Therapy consisted of 8 cycles R-GemOx (arm A) or 8 cycles of nivolumab plus R-GemOx followed by nivolumab as maintenance for up to 1 year in total or until progression or unacceptable toxicity (arm B). The primary endpoint was progression-free survival (PFS) after 1 year. Major secondary endpoints were response rates, event-free- (EFS) (time to progression, relapse, death or unplanned anti-lymphoma treatment), overall survival (OS) and toxicity. The protocol specified a pre-planned interim analysis after the first 180 pts completed up to at least 1 follow-up investigation. Results: Between Jan 2018 and May 2021, 180 pts were randomized. Two pts did not receive any treatment (one withdrawn informed consent, one death) resulting in a full analysis set of n=90 (arm A) and n=88 (arm B). Median age was 76 years (range 44-87), 52% of pts were &amp;gt;75 years of age, 37% were primary progressive after first-line therapy, 62% had IPI 3-5. Overall response (OR) and complete response (CR) rates were similar with 34% and 20% (arm A) vs. 34% and 22% (arm B), respectively. Rates of progressive disease (PD) were 53% (arm A) vs. 50% (arm B). After a median follow-up of 21 months, 1-year PFS was 28% (95%-CI: 18%-37%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.827) in arm B (Figure A). 1-year EFS was 22% (95%-CI: 13%-31%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.654) in arm B. One-year OS was 48% (95%-CI: 38%-59%) in arm A vs. 58% (95%-CI: 47%-68%), (p=0.126) in arm B. At 2 years, PFS, EFS and OS were 15% (95%-CI: 6%-24%), 13% (95%.CI: 5%-21%) and 34% (95%-CI: 22%-46%) in arm A vs. 15% (95%-CI: 7%-23%), 15% (95%-CI: 7%-23%) an 43% (95%-CI: 32%-55%) in arm B. Because of an identical PFS but a trend toward better OS for arm B, we performed an event-driven OS analysis of pts after second progression or relapse (n=70 in arm A, n= 73 in arm B). OS survival was superior in arm B vs. arm A after second progression or relapse (Log Rank p= 0.010) (Figure B). There was a small increase in number of pts with grade 3-5 AEs in arm B (arm A/arm B: thrombocytopenia 37%/39%; anemia 19%/26%; leukopenia 19%/24%; infection 15%/22%). No increase in number of pts with immune-related grade 3-5 AEs was observed except asymptomatic increase of lipase (arm A/arm B: 23%/27%), (p=0.625) and amylase (arm A/arm B: 5%/11%), (p=0.192). Most common grade 3-5 AEs during nivolumab consolidation in arm B were leukopenia 13%, peripheral neuropathy 10%, increase of lipase 8%, anemia 5% and infection 5% of pts). In total, 7 treatment-related deaths occurred (arm A/arm B: 3 (3%)/4 (5%). After this interim analysis revealed futility to demonstrate superiority for the primary endpoint, recruitment was stopped in March 2023. At that point, 270 of 310 initially intended pts had been recruited. Conclusions: In pts with R/R LBCL, the addition of nivolumab to R-GemOx followed by nivolumab maintenance is feasible without relevant additive toxicity. The addition of Nivolumab did not improve PFS of the R-GemOx regimen alone. These results demonstrate the poor prognosis of R/R transplant-ineligible pts treated with immuno-chemotherapy. However, a trend towards a better OS was observed, which allows for the hypothesis that nivolumab might enhance the efficacy of subsequent therapies. The final analysis of the study is scheduled after completion of follow-up of the last patient included as defined by the study protocol.

Larval digestive system ontogeny and early weaning in neon tetra Paracheirodon innesi.

The intensive culture of characid teleosts for ornamental trade is highly dependent on live feed organisms, particularly Artemia nauplii, to provide nutrition through the larval stage. Live feeds have inherent disadvantages relative to prepared microparticulate diets (MDs), specifically availability, labor and cost. In this research, the dependence of larval Paracheirodon innesi on live Artemia was confirmed via a nutritional trial. Next, digestive system ontogeny was characterized from the onset of exogenous feeding through metamorphosis. P. innesi exhibited an agastric larval stage, as well as low digestive enzyme activity at the onset of exogenous feeding followed by abrupt increases in trypsin, lipase and pepsin activity. Differentiation of the stomach, including gastric gland formation and production of neutral mucopolysaccharides, as well as the onset of pepsin activity, did not occur until 20days post hatch (dph; 5.24 ± 0.20mm). This shift from agastric to gastric digestive modes is indicative of a proliferation of digestive capacity and subsequent prey diversity in other fish species exhibiting similar altricial larval stages.Based on this information, different schedules for weaning from Artemia to a MD were evaluated. For P. innesi fed until 32 dph, weaning beginning at 12 dph and 17 dph resulted in similar survival to live Artemia (mean: 22.0 ± 1.7%), and the MD resulted in the lowest survival (0.8 ± 0.3%). These results indicate that weaning is possible prior to gastric differentiation, potentially resulting in the reduction of Artemia use in the larval culture P. innesi.

FRI657 Case Series On GLP-1 Receptor Agonist Related Acute Pancreatitis

Abstract Disclosure: A.U. Kulkarni: None. V. Mehta: None. M. Renzu: None. K. Pereira: None. M.A. Rather: None. Introduction: Acute pancreatitis (AP) has now become one of the leading causes of GI related hospital admissions in the United States. With increasing use of GLP-1 Receptor Agonists (GLP-1 RA) in T2DM and obesity, they are now being identified as one such class of drugs which can cause AP. We present this case series to discuss these adverse effects. Case 1: A 50 yo AA male with a history of T2DM and hypertension presented with acute severe epigastric pain, nausea and vomiting for 5 days. Vitals were stable. On physical exam, tenderness in the RUQ was noted. Labs revealed lipase of 313 U/l (11-82 U/l), BG of 213 mg/dL, HbA1c 11.3, normal LFT and lipid panel. Blood EtOH was negative. He denied tobacco, alcohol, and illicit drug use. CT abdomen showed acute interstitial edematous pancreatitis without cholelithiasis or choledocholithiasis. Liver ultrasound showed hepatic steatosis. He noted recent initiation of Semaglutide 6 months ago which was stopped 3 weeks prior to this visit due to abdominal discomfort. Previous Dulaglutide therapy was also discontinued due to GI intolerance. Home medication for DM otherwise included metformin and basal insulin. Case 2: A 68 yo AA woman with a history of T2DM, hypothyroidism presented after a week of severe epigastric pain, radiating to her back, with nausea and vomiting. Labs showed lipase 593 U/l (11-82 U/l), BG of 427 mg/dl, HbA1c of 10. Social history was non-contributory. CT Abdomen showed AP and no gallstones or bile duct dilatation. LFTs and lipid panel were unremarkable. Chart review noted prior admission for AP a month ago. Her home medications were basal Insulin and Dulaglutide (4 yrs). Drug induced AP from Dulaglutide was suspected. Lack of clinical improvement after 3 days of management prompted RUQ ultrasound, which was prematurely terminated due to pain during the scan. Subsequent CCK-HIDA was negative for acute cholecystitis but noted low gallbladder EF. Thus dulaglutide was identified as a potential trigger along with gallbladder dysmotility as a possible etiology for her recurrent AP. Both patients were managed with IV fluids, NPO diet and morphine. They were instructed to stop GLP-1 RA and discharged with PCP follow-up. Discussion: GLP-1 RA are now being widely used due to low risk of hypoglycemia and weight loss. Clinical trials with GLP-1 RA have shown mild, asymptomatic increase in lipase, amylase levels as well as rare incidences of AP. This has been attributed to the stimulation of pancreatic beta cells and exocrine duct cells leading to acinar cell hypertrophy, proinflammatory cytokine induction, causing pancreatic injury. Though drug-induced AP is uncommon and is a diagnosis of exclusion, detailed history taking, medication review and investigating for all other causes is of utmost importance. A good understanding of the drugs associated with AP should alert the physician to identify these agents and promptly discontinue them to prevent further complications. Presentation: Friday, June 16, 2023

Phase II study of capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer: the PANDORA trial

This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer. The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (α= 0.05, power= 0.80). The proposed treatment could be considered promising if ≥13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365). Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation.