Increase In ALT Research Articles

Abstract CT189: PRTX007, an optimized TLR7 agonist for systemic immunotherapy of cancers: Interim analysis of phase I study in healthy volunteers

Abstract Background. Toll-like receptor 7 (TLR7) agonists have long been recognized as potential systemic anti-cancer immunotherapy agents. However, clinical development has been limited by complex target-mediated pharmacology including those associated with elevated levels of proinflammatory factors, which also limit the ability to combine with immune checkpoint inhibitors (CPI). PRTX007 is an orally administered prodrug of PRX034, a novel TLR7 agonist that elicits IFN-mediated immune induction without inducing inflammation via the NF-κβ pathway. QOD dosing in primates maintains a stable immune response without immune exhaustion or toxicity. Efficacy, safety, and compatibility with immune CPI were demonstrated in a CT26 syngeneic rodent tumor model. Methods. We conducted a phase 1, single-center, prospective, randomized, double-blind placebo-controlled study of 8 single-ascending dose (SAD) and 4 multiple-ascending dose (MAD) cohorts of PRTX007 administered orally to healthy adult participants. Primary objectives were safety and tolerability. Secondary objectives were evaluation of pharmacokinetics (PK) and pharmacodynamics. This interim analysis focuses on the 8 SAD (50-600 mg) and 2 MAD (300-400 mg) cohorts, with 64 of the 84 participants in the study receiving drug. Results. Treatment-related adverse events include non-dose‒related mild headache, and minor dose-related increases in ALT (<2X ULN) that rapidly resolved. The PKs of PRTX007 and PRX034 are well-behaved eg, exposure increasing proportionally with PRTX007 dose. Consistent with studies in human cells in vitro and non-human primates in vivo, oral administration of PRTX007 elicits systemic TLR7-mediated immune induction without engaging NF-κβ─mediated biosynthesis of IL-6, TNFα and IL-1β in humans. A single dose of PRTX007 (300-600 mg) elicits coordinated expression of IFN-stimulated genes (ISGs) in blood without quantifiable increases in circulating IFNs. At 500 and 600 mg doses, IP-10, IL-1RA, MCP-1 and TRAIL but not IL-6, TNFα or IL-1β increase in plasma (maximal response = 4020, 1460, 650 and 360 pg/ml, respectively). When PRTX007 is administered for 2 weeks on a QOD schedule at 400 mg/dose, the degree of ISG expression progressively increases when compared to the first-dose response, (eg, ISG15 increases 2.1-fold [geometric mean] following Dose 1 vs pretreatment baseline, rising to 12.2-fold following Dose 7). This is accompanied by modest activation of circulating NK, B, and CD4+ and CD8+ T cells as measured by cell-surface markers. IL-6, TNFα and IL-1β remain unchanged from pretreatment levels. Conclusion. At the interim analysis, PRTX007 demonstrated a favorable safety profile when administered orally to all tested SAD and MAD cohorts. Dose-dependent systemic exposure was observed, as well as activation of the innate immune response, without production of proinflammatory factors. Citation Format: Charlotte Lemech, Christopher Argent, Curtis Scribner, Richard Daniels, James Richard Appleman. PRTX007, an optimized TLR7 agonist for systemic immunotherapy of cancers: Interim analysis of phase I study in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT189.

Abstract CT196: Early results of a safety and efficacy study of allogeneic TruUCAR™ GC502 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL)

Abstract Introduction: CD19 targeted autologous CAR-T therapies have been approved for the treatment of r/r B-ALL and greatly improved outcome. However, some patients may not be eligible to receive autologous CAR-T. TruUCAR™ GC502 is an allogeneic, universal CAR-T product with CD19/CD7 dual directed CAR. Preclinical data of GC502 were reported at ASH 2021 (Abstract 148500). Here, we report early clinical results from a phase I open-label, non-randomized, prospective investigator initiate trial (IIT) of GC502 in r/r B-ALL patients. Methods: GC502 is manufactured using leukopaks from HLA-unmatched healthy donors. It contains a 4-1BB based CD19/CD7 dual directing CAR, a T cell enhancer, and genetically disrupted TRAC and CD7 loci to avoid GvHD and fratricide. Patients (pts) with r/r B-ALL were enrolled and treated with one of two different formulations (A or B) in escalating dose levels ranging from 1.0x107 (DL1) to 1.5x107 (DL2) cells/kg. Prior to infusion of GC502, pts received a Flu/Cy based lymphodepletion regimen. Adverse events, disease response and expansion kinetics were evaluated in this study. Results: To date, 4 pts (15-34 yrs) were enrolled from Sep. 2021 to Jan. 2022. All patients were heavily pretreated, and had received either autologous or donor derived CD19 or CD19-CD22 targeted CAR-T therapy. Baseline marrow blast levels ranged from 19.5% to 92% (median 48.1%). 1 pt had extramedullary involvement. At data cut-off (Jan. 28, 2022), all patients had received a single dose of GC502: 1 pt at DL 1 1.0x107cells/kg and 3 patients at DL 2 1.5x107cells/kg. At day 28 post CAR-T infusion, 2 out of 3 response evaluable patients had achieved CR/CRi; 1 pt achieved PR at month 1 and subsequently received HSCT on day 39. TEAEs presented as Gr 3 febrile neutropenia (2/3), Gr 4 thrombocytopenia (1/3) and Gr 3 anemia (3/3). All TEAE resolved after treatment with SOC. Non-hematological TEAE presented as Gr≤3 γ-GT increase (3/3), Gr≤3 AST increase (2/3) and Gr≤3 ALT increase (3/3). CRS presented as Gr 2 in 2 patients with formulation B. 2 pts received formulation A and experienced Gr 3 CRS with a duration of 7 and 10 days respectively (CRS was graded according ASTCT Consensus Grading). CRS in all pts was manageable and resolved after treatment with Ruxolitinib, SOC and supportive care. No ICANS or aGvHD were observed. The pt treated in DL 1 did not show adequate GC502 cellular expansion. Peak expansions of GC502 in peripheral blood were observed between week 1-2 in DL 2. Median peak CAR copies were 149,945 copies/ug DNA (range 10,849-195,400). Conclusions: TruUCAR™ GC502 demonstrated promising early results with a manageable safety profile. Robust CAR-T cell expansion was observed in DL2 at 1.5x107cells/kg in heavily pretreated r/r B-ALL patients, including those previously treated with CD19 CAR-T therapies. The study is ongoing and continues accruing patients. Citation Format: Shiqi Li, Xinxin Wang, Zhongtao Yuan, Lin Liu, Yu Li, Jia Liu, Jiaping He, Zhimin Li, Wei Zhao, Jianning Ge, Yajin Ni, Lianjun Shen, Wei Cao, Xi Zhang, Martina Sersch, Sanbin Wang. Early results of a safety and efficacy study of allogeneic TruUCAR™ GC502 in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT196.

Abstract CT034: Phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study)

Abstract Background: METex14 mutations was reported in 3~4% of NSCLC patients and became a new target in the treatment of NSCLC. SCC244 is a highly selective and potent oral MET inhibitor. This is the first report of data from an ongoing single-arm phase II study of SCC244 in NSCLC patients with METex14 mutations (GLORY study). Methods: GLORY study is an open label, international, multi-center, single-arm phase II study to evaluate the efficacy and safety of SCC244 in patients with locally advanced or metastatic NSCLC harboring METex14 mutations which was confirmed by central laboratory. The enrolled patients have either failed one or two prior lines of systemic therapies or been not eligible/refused chemotherapy after being well-informed. SCC244 was taken orally at a dose of 300 mg once daily in 21-day treatment cycles until disease progression or intolerable toxicity. Tumor was evaluated every 6 weeks for the first 8 treatment cycles and every 9 weeks thereafter. The primary endpoint was objective response rate (ORR) assessed by blinded independent review committee (BIRC) per RECIST 1.1, secondary endpoints include ORR by investigator assessment (INV), duration of response (DoR), time to response (TTR) and safety etc. Post-hoc analysis was done to explore the intracranial anti-tumor activity. Results: At data cut-off on May 6th, 2021, a total 73 patients screened from 163 patients in 42 sites were treated at 300 mg QD dose and had ≥2 post-baseline tumor assessments or discontinued for any reason. 69 of them were with METex14 mutation confirmed by central laboratory. In the 69 patients, ORR by BIRC was 60.9% (95% CI: 48.4%, 72.4%) overall, 66.7% (95% CI: 50.5, 80.4) and 51.9% (95% CI: 31.9, 71.3) in treatment naïve and previously treated patients respectively. Median DoR was 8.2 months (95% CI: 4.8, NE) and median PFS was 7.6 months (95% CI: 4.2, NE), tumor response from 30 of 42 responders was still ongoing. The response occurred fast with a median TTR of 1.4 months (range: 1.2, 4.2). Partial response was observed in 8 of 10 patients with brain metastasis. 5 patients who had brain metastasis selected as targeted lesion had intracranial response by INV with a median intracranial tumor shrinkage of 57% (range: 34%, 71%). The most common (≥20%) treatment-related adverse events (TRAEs) of any grade were peripheral edema, headache, nausea, loss of appetite, hypoalbuminemia, ALT increase and vomiting. The incidence of ≥ grade 3 TRAEs was 43.8%. TRAEs leading to treatment discontinuation occurred in 6.8% patients, among which peripheral edema was the most common (4.1%). Conclusions: The data shows high and robust efficacy of SCC244 in NSCLC patients with METex14 mutations across treatment lines and encouraging intracranial anti-tumor activity. The safety profile was favorable with manageable toxicity. The data supports SCC244 as a valuable targeted treatment option for METex14 NSCLC patients. Citation Format: Shun Lu, Yongfeng Yu, Jianya Zhou, Koichi Goto, Xingya Li, Jun Sakakibara-Konishi, Kazumi Nishino, Tanaka Kentaro, Lin Wu, Xuhong Min, Wei Zhang, Dingzhi Huang, Yongqian Shu, Chengzhi Zhou, Min Li, Xiaorong Dong, Chong Bai, Lu Li, Jiuwei Cui, Li Zhang, Lejie Cao, Xiaoling Li, AiMin Zang, Haruki Kobayashi, Yiping Zhang, Yan Yu, Xiuwen Wang, Terufumi Kato, Shoichiro Yamamoto, Yuki Shinno, Xiaoyan Lin, Yanqiu Zhao, Yanping Hu, Qitao Yu, Ziping Wang, Masahiro Kodani, Jian Fang, Jialei Wang, Meiqi Shi, Diansheng Zhong, Wen Dong, Hiroshi Tanaka, Yasuto Yoneshima, Minghui Sun, Jun Zhou, Qiuxia Wu, Meng Li. Phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT034.

Acute and sub-chronic toxicity study of the mixture of Calotropis procera (Ait). R. Br. (Apocynaceae) and Zanthozylum zanthozyloïdes Lam. (Rutaceae) roots bark powder

In Burkina Faso, sickle cell syndromes affect 8.42% of hospital patients. For the management of sickle cell anemia, a phytomedicine called FACA® capsules based on a mixture of roots barks powdered from Calotropis procera and Zanthozylum zanthozyloïdes has been developed. The objective of this study was to evaluate the acute and sub-chronic toxicity of this mixture. Toxicity studies were conducted according to OECD guidelines on Wistar rats. The acute toxicity test estimated the LD50 to be 5000 mg/kg body weight. The sub-chronic toxicity study showed a significant dose-dependent decrease in food consumption; and the body weight gain of the treated rats. Biochemical analysis showed a significant decrease in the level of serum total protein and cholesterol and an increase of ALT and blood sugar levels at 500 and 1000 mg/kg. A significant decrease in the number of red blood cells and hemoglobin have been observed at 1000 mg/kg. Histopathological examination of the organs shows atrophy of the muscle wall and destruction of the epithelial surface of the stomach at 1000 mg/kg body weight. Based on these results, this mixture does not exhibit acute oral toxicity and could be well tolerated at therapeutic doses (17.5 mg/kg).

A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma.

4519 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). A phase II clinical study showed that RC48-ADC has a good effect on locally advanced or metastatic urothelial carcinoma with HER2-positive expression that failed standard chemotherapy. In the study, some patients with HER2-postive immunohistochemistry (IHC 2+) but negative FISH test still benefited from the treatment of RC48-ADC.This study was to evaluate the activity and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. Methods: This study is an open-label, single-center, single-arm, phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1,and treated with ≥1 prior systemic treatment. Patients received RC48-ADC 2mg/kg q2w until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. The primary objectives were activity (ORR) and safety. Second objectives included progress-free survival, disease control rate and overall survival. Results: As of February 2022(date cutoff),19 patients were enrolled. The median age was 64 years old(range:36-77). At baseline, there were 6 patients with HER2(IHC 0), and 13 patients with HER2(IHC 1+).Most patients (13/19) had visceral metastasis. 15(79%) patients had received≥2 lines treatment.At date cutoff, 19 patients were assessable for response. The objective response rate was 26.3% (95% CI:9.1%,51.2%) and the DCR was 94.7% (18/19). The mPFS was 5.5months (95% CI:3.9,6.8) and mOS was 16.4months (95% CI:7.1,21.7).All of the 6 patients with HER2(0) were SD in the study. The ORRs were 38% (5/13) in patients with HER2(IHC 1+),31% (4/13) in visceral metastasis,17% (1/6) in liver metastasis patients,27% (4/15) in patients post to ≥ 2 lines of treatment. Common treatment-related AEs were leukopenia (52.6%), hypoesthesia (47.4%),alopecia (47.4%), AST increase (42.1%), ALT increase (42.1%), and neutropenia (42.1%), fatigue (42.1%),nausea (26.3%), vomiting (15.8%).Most of these AEs were Grade 1 or 2. The AE of Grade 3 was neutropenia (10.5%). The SAE was CPK increased (5.3%). Conclusions: This study showed that RC48-ADC was safe and the ORR was 26.3% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. The enrollment was completed and data will be updated later. Clinical trial information: NCT04073602.

A randomized phase Ib/II study of niraparib (nira) plus nivolumab (nivo) or ipilimumab (ipi) in patients (pts) with platinum-sensitive advanced pancreatic cancer (aPDAC).

4021 Background: Establishing alternatives to perpetual chemotherapy for pts with aPDAC has been proposed to address inevitable chemotherapy resistance and cumulative toxicity. Poly (ADP ribose) polymerase (PARP) inhibitors have shown clinical efficacy in this setting, and preclinical data suggest that the addition of immune checkpoint blockade (ICB) may offer synergistic tumor control. We performed a randomized, phase Ib/II study of nira plus anti-PD-1 (nivo) or nira plus anti-CTLA-4 (ipi) maintenance for pts with aPDAC who had not progressed after >4 mo of platinum-based therapy. Methods: After discontinuation of chemotherapy, pts were randomized 1:1 to nira 200mg PO daily plus either nivo 240mg IV q2 weeks (later amended to 480mg IV q4 weeks) or ipi 3mg/kg IV q3 weeks for four doses. Nira could be escalated to 300mg PO daily if tolerated. Pts were treated until progression or unacceptable toxicity. The primary endpoint was progression free survival at six months (PFS6) in each arm. Secondary endpoints included safety, OS, ORR, and outcomes by DNA damage repair (DDR) deficiencies. Pts were evaluable for safety if they had received > 1 dose of study treatment and for efficacy if they had also received > 1 follow-up imaging study. Based on historical data, the null hypothesis of PFS6 = 44% vs a 2-sided alternative hypothesis of PFS ≠ 44% was tested. 42 pts per arm provided 81% power for testing at a 5% significance level to detect inferior PFS6 < 27% or superior PFS6 > 61%. Results: As of Oct 2021, 91 pts were enrolled, of whom 84 were evaluable for efficacy (44 nira/nivo; 40 nira/ipi). The median potential follow-up was 23 mos. Most common treatment-related AEs were nira/nivo: thrombocytopenia (28%), arthralgia (25%), nausea (23%), and fatigue (23%) and nira/ipi: thrombocytopenia (45%), anemia (43%), fatigue (43%), nausea, (41%), AST increase (36%), rash (34%) and ALT increase (29%). 88% of AEs were grade 1-2. Efficacy results were: nira/nivo: PFS6 20.6% (95% CI 8.3-32.9, p = 0.0002), mPFS 1.9 mo and nira/ipi: PFS6 59.6% (95% CI 44.3-74.9, p = 0.045), mPFS 8.1 mo. Fifteen pts (8 nira/nivo; 7 nira/ipi) had pathogenic variants in BRCA or PALB2 . Excluding these: mPFS on nira/nivo was 1.9 mo (95% CI 1.8-1.9) and mPFS on nira/ipi was 7.6 mo (95% CI 4.0 – 11.1). Conclusions: In a randomized phase 1B/II study, nira/ipi as maintenance therapy met the primary endpoint of superior PFS6 while nira/nivo yielded inferior PFS6 for pts with aPDAC who had not progressed on first-line platinum-based chemotherapy. The benefit of nira/ipi maintenance persisted in pts without known DDR variants. Clinical trial information: NCT03404960. [Table: see text]

Efficacy and safety of sintilimab plus XELOX as neoadjuvant therapy in patients with locally advanced gastric cancer: A single-arm open-label phase II trial.

e16091 Background: Neoadjuvant chemotherapies have been widely recommended by clinical guidelines for patients with locally advanced gastric cancer. However, the evidence of combining neoadjuvant chemotherapy with anti-programmed death 1 (anti-PD-1) antibody therapy for patients with locally advanced gastric cancer is inadequate. Thus, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anti-PD-1 antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in patients with locally advanced gastric adenocarcinoma. Methods: Patients with locally advanced(cT3-4 N+ M0, CY0,P0) were enrolled and received four preoperative cycles of XELOX (oxaliplatin 130mg/m2, IV, d1 with capecitabine 1000mg/m2, bid, d1-d14, q21d) and sintilimab (200mg, IV, q21d). Surgery was performed within 3-4 weeks after completion preoperative therapy. After surgery, patients received four cycles of XELOX. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoints were major pathologic response (MPR) rate, R0 resection rate, safety, disease-free survival (DFS) and overall survival (OS). This clinical trial is registered at ChiCTR.gov.cn: ChiCTR2000030414. Results: From March 2020 to July 2021, 30 patients were enrolled, with median age 62 years (range30-72), males 18, cT3/T4: 8/22, cN1/2/3: 10/14/6, intestinal diffuse type (Lauren classification):17/13, ECOG PS 0/1/2: 19/8/3. There were 19(63.3%) patients with PD-L1 CPS≥1. All patients were available for preoperative response evaluation, the objective response (ORR) rate was 70.0% (95% CI, 50.6%-85.3%) and the disease control (DCR) rate was 100% (95% CI, 88.4%-100%). All (100%) achieved R0 resection. 10 patients (33.3%) achieved pCR (TRG 0) and 19 patients (63.3%) had MPR (TRG 0-1). Common treatment-related adverse events (TRAEs) were anemia (36.7%), leukopenia (36.7%), neutropenia (30.0%), diarrhea (26.6%), ALT increase (23.3%), AST increase (13.3%), thrombocytopenia (10.0%), vomiting (10.0%). The potential immune-related adverse events (irAEs) were dermatitis (6.7%), hypothyroidism (3.3%), pneumonia (10.0%). Most of the TRAEs and potential irAEs were grade 1 or 2. Grade3 TRAEs and irAEs included ALT increase (3.3%), AST increase (3.3%), dermatitis (3.3%). There were no severe complications and death related to the operation. The median postoperative hospital stay was 8 days (range6-23 days). Conclusions: Sintilimab plus XELOX as neoadjuvant therapy showed an encouraging pCR rate, MPR rate and manageable safety. This combination regimen might provide a new option for patients with locally advanced gastric cancer. Clinical trial information: ChiCTR2000030414.

First-in-human/phase I trial of PE0116 (4-1bb Ig G4 McAb) as single agent in patients with solid tumors progressed after lines of therapies in China.

2640 Background: The 4-1BB co-stimulatory protein is an important modulator of the adaptive T Cell immune responses, and potentially a vital target for immunotherapies in oncology. HE0116 is a humanized agonist antibody to 4-1BB that promotes proliferation and activation of T cells. The FIH/phase Ia/Ib study was conducted to establish a maximum tolerated dose, identify dose-limiting toxicities (DLTs) and to assess safety, tolerability, and pharmacokinetics of HE0116 as single agent in patients with solid tumors who have progressed on standard of care (SoC) and experimental therapies. Methods: Patients (pts) with histologically confirmed solid tumors who progressed after prior SoC and experimental therapies were enrolled. A Fibonacci 3+3 design was employed for the phase 1a dose escalation of 9 dose levels. HE0116 was administered intravenously once in first 28-day cycle for PK analysis and DLT assessment. Pts continued HE0116 treatment every 3 weeks until experiencing an intolerable toxicity, disease progression or withdrawing consent. Results: As of January 25, 2022, 19 pts were enrolled in the dose-escalation phase). All pts had progressed on multiple lines of therapies, including but not limited to, chemotherapy, hormonal therapy, or/and immunotherapy. As defined in study protocol, pts received HE0116 intravenously at least once at six dose levels: 0.03 mg/kg (n = 1), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3), 1 mg/kg (n = 4), 2 mg/kg (n = 3), and 3 mg/kg (n = 5). One DLT of Grade (g) 4 platelets decrease was reported at 3 mg/kg, thus 3 new pts were added at this dose. The grade1 and grade2 HE0116 related adverse events (AEs) per CTCAE v5 that occurred ( < 10% frequency) were ALT and AST increase, platelet decrease, WBC decrease, anemia, hypokalemia, hyponatremia, hypoalbuminemia, hypothyroidism, or bone pain. Three SAE were reported: 1 g2 ascites, 1 g4 dyspnea, 1 g2 fever. To date there was one iPR at 1 mg/kg for a pt with advanced ovarian cancer with liver met after 6 cycles of treatment, and 4 iSD (1 in 2 mg/kg, 3 in 3 mg/kg) were recorded. Conclusions: HE0116 administrated intravenously every 3 weeks is well tolerated with minimal toxicities. Preliminary data are very encouraging as single agent HE0116 showed durable responses with 1 iPR, 4 iSD in several difficult to treat late-stage cancer pts. Dose escalation is ongoing as per study protocol. Phase II in select patient populations, and clinical investigation of the combination of HE0116 with CTLA-4 or PD-1 are warranted. Clinical trial information: CTR20201794.

Experimental assessment of the toxicity of a cardiac drug based on a phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate

The study aimed to establish the parameters of chronic toxicity of the newly developed drug based on phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate in experiments on laboratory animals. The analysis was performed on white sexually mature young male Wistar rats weighing 170–185 g. Four groups of white rats were formed. The first experimental group was administered Bendamine based on a phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate at a therapeutic dose. Rats of the second experimental group were injected with the experimental drug in a 5-fold dose. Rats of the third experimental group were administered the drug in a 10-fold dose. The fourth group served as control. The study of chronic toxicity of Bendamine in white rats indicates that long-term 30-day administration in therapeutic doses or 5-fold dose does not cause clinical signs of poisoning, as evidenced by the physiological limits of fluctuations in the studied morphological and biochemical parameters of blood rats. Prolonged administration of Bendamine to rats in a 10-fold dose is accompanied by a slight suppression of the body's physiological state, as indicated by a decrease in total erythrocytes and hemoglobin by 10.1 % against an increase in white blood cells by 59.8% (P < 0.001). In addition, there was a decrease in the functional state of the liver, as evidenced by a probable reduction in total protein by 8.0% and urea – by 13.5 %, as well as an increase in ALT, AST, and alkaline phosphatase by 31.6 %, 7.4 %, and 53.9% respectively. Probable changes in the coefficients of liver and spleen mass have been established. When administered intramuscularly to rats with the drug Bendamine for 30 days, the macroscopic and microscopic structure of the studied internal organs is preserved in all groups of animals. The second experimental group revealed reversible moderate histostructural changes in the liver and kidneys. In rats treated with ten times the therapeutic dose of the drug, histologically found hemodynamic disorders and alterations in dystrophic nature, mainly of protein origin, with focal localization in the parenchyma of the liver, kidneys, and myocardium, which in most cases are reversible and result from the compensatory response. Macroorganism on the introduction of a high dose of the study drug.

TELOMERE LENGTH AS A BIOLOGICAL MARKER FOR ASSESSING THE SERIOUSNESS OF PNEUMONIA OF VARIOUS ETIOLOGIES

Abstract. The results of the features of the clinical course of pneumonia of various etiologies are presented, taking into account the epigenetic indicator of the human body, such as telomere length. We examined 102 male military personnel who were treated at the hospital therapy clinic of the Military Medical Academy named after S. M. Kirov. The patients were divided into two groups: group I of 63 people aged 37,3±6,7 years with pneumonia caused by a new coronavirus infection; Group II - 39 men aged 41.4±5.3 years with bacterial pneumonia of various etiologies. Patients were examined and treated according to the standard scheme. In the group of severe viral pneumonia, a significantly larger volume of lung parenchymal damage was determined, a decrease in saturation to 91,3±1,6% (p=0,003); myocardial damage: an increase in troponin T up to 15,6±5,3 ng/l (p=0.001), an increase in total CPK, AST and ALT compared with patients of group II. In group I, evaluating the results of hemogram parameters, attention is drawn to the tendency to thrombocytopenia (172±29x109/l, p=0,03), the tendency to leukopenia (4.1±1,2x109/l) in severe disease. There was a significant increase in CRP, D-dimer and ferritin in severe viral pneumonia in men of group I, which can be characterized as coagulopathy associated with the risk of developing arterial and venous thrombosis because of microthrombovasculitis. Telomeres are specialized functional complexes that are located at the ends of chromosomes and protect them from fusion with each other, which preserves the integrity of the eukaryotic cell genome. Telomere length is an important characteristic of a person’s overall health. It is associated with such characteristics as longevity or the affinity of the human body to various diseases, such as type 2 diabetes mellitus, hypertension, coronary heart disease, and others. In this scientific study, change in length lomer in patients with pneumonia of various etiologies. The most pronounced shortening of telomere length was found in patients with severe viral pneumonia (significant shortening of telomere length by more than 2000 base pairs), compared with bacterial pneumonia. The identified changes can be used to predict an unfavorable outcome of pneumonia caused by a new coronavirus infection, for example, the development of such a formidable complication as a “cytokine storm”. The obtained preliminary results make it possible to consider telomere length as a specific biological marker for assessing the severity of pneumonia caused by the SARS-CoV-2 virus.

CHANGES IN SOME HAEMATOLOGICAL AND BIOCHEMICAL PARAMETERS IN LOCAL BLACK GOATS DURING PREGNANCY

The present study was aimed to assess and determine the effects of pregnancy on some biochemical and haematological parameters. This experiment was conducted using 16 pregnant of known gestational period and 4 non-pregnant does raised at commercial farm. Results revealed a non-significant differences between pregnant and non-pregnant does for all studied traits. With the advances of pregnancy, it was noticed an increase (P<0.05) in PCV, Hb, AST, ALT, Glucose and Cholesterol and a decrease in total protein and globulin. In conclusion, it can be indicated that physiological status impacts the traits under consideration.

First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: A phase I/II study evaluating efficacy and safety

360490 Background: KRAS mutation is present in 90% of pancreatic ductal adenocarcinomas with p.G12C accounting for 1% to 2% of these mutations. Sotorasib, a small molecule that specifically and irreversibly inhibits KRASG12C, has been investigated in the CodeBreaK100 trial in patients with KRASG12C-mutated advanced solid tumors. Herein, we report on the largest dataset evaluating efficacy and safety of a KRASG12C inhibitor in patients with pretreated KRASG12C-mutated pancreatic cancer. Methods: CodeBreaK100 (NCT03600883) is an international, single arm, phase I/II study evaluating the efficacy and safety of sotorasib in patients with KRASG12C-mutated advanced solid tumors with ≥ 1 prior systemic therapy unless intolerant or ineligible for available therapies. The primary efficacy endpoint is confirmed objective response rate (ORR), assessed by blinded independent central review (BICR) per RECIST 1.1. Secondary endpoints include duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: As of November 1, 2021, 38 patients with pancreatic cancer (mean age: 65 years, 76.3% male) from the combined phase I/II study received sotorasib 960 mg once daily. Stage IV disease was present in 55.3% of patients at diagnosis, and in all patients at enrollment. Baseline ECOG scores were 0, 1, or 2 in 31.6%, 57.9%, and 10.5% of patients, respectively. Most patients (79%) had ≥ 2 prior lines of therapy (median: 2 [range: 1-8]). Median treatment duration was 4.1 months with a median follow-up of 16.8 months. Eight patients had confirmed partial response by BICR with a resulting ORR of 21.1% (95% CI: 9.55%-37.32%). DCR was 84.2% (Table 1). Treatment-related adverse events (TRAEs) of any grade occurred in 16 (42.1%) patients. Grade ≥ 3 TRAEs occurred in 6 patients: diarrhea (2); fatigue (2); abdominal pain, ALT increase, AST increase, pleural effusion, and pulmonary embolism (1 each). No TRAEs were fatal or resulted in sotorasib discontinuation. Conclusions: Sotorasib demonstrated clinically meaningful anticancer activity and tolerability in patients with heavily pretreated KRASG12C-mutated advanced pancreatic cancer, who have limited treatment options and poor prognosis. Clinical trial information: NCT03600883. [Table: see text]

Suppression of Oxidative Stress and Proinflammatory Cytokines Is a Potential Therapeutic Action of Ficus lepicarpa B. (Moraceae) against Carbon Tetrachloride (CCl4)-Induced Hepatotoxicity in Rats.

Local tribes use the leaves of Ficus lepicarpa B. (Moraceae), a traditional Malaysian medicine, as a vegetable dish, a tonic, and to treat ailments including fever, jaundice and ringworm. The purpose of this study was to look into the possible therapeutic effects of F. lepicarpa leaf extract against carbon tetrachloride (CCl4)-induced liver damage in rats. The DPPH test was used to measure the antioxidant activity of plants. Gas chromatography-mass spectrometry was used for the phytochemical analysis (GCMS). Six groups of male Sprague-Dawley rats were subjected to the following treatment regimens: control group, CCl4 alone, F. lepicarpa 400 mg/kg alone, CCl4 + F. lepicarpa 100 mg/kg, CCl4 + F. lepicarpa 200 mg/kg and CCl4 + F. lepicarpa 400 mg/kg. The rats were euthanized after two weeks, and biomarkers of liver function and antioxidant enzyme status were assessed. To assess the extent of liver damage and fibrosis, histopathological and immunohistochemical examinations of liver tissue were undertaken. The total phenolic content and the total flavonoid content in methanol extract of F. lepicarpa leaves were 58.86 ± 0.04 mg GAE/g and 44.31 ± 0.10 mg CAE/g, respectively. F. lepicarpa’s inhibitory concentration (IC50) for free radical scavenging activity was reported to be 3.73 mg/mL. In a dose-related manner, F. lepicarpa was effective in preventing an increase in serum ALT, serum AST and liver MDA. Histopathological alterations revealed that F. lepicarpa protects against the oxidative stress caused by CCl4. The immunohistochemistry results showed that proinflammatory cytokines (tumour necrosis factor-α, interleukin-6, prostaglandin E2) were suppressed. The antioxidative, anti-inflammatory, and free-radical scavenging activities of F. lepicarpa can be related to its hepatoprotective benefits.

Temporal analysis of paracetamol-induced hepatotoxicity

Paracetamol-induced hepatotoxicity (APAP) causes severe damage that may be irreversible. Understanding the evolution of liver injury caused by overdose of the drug is important to assist in the treatment. In the present study, we evaluated the acute intoxication by APAP (500 mg/kg) in periods of 3 and 12 hours in C57BL/6 mice through biochemical, histological, inflammatory parameters, and the redox status. The results showed that in the 3-hour period there was an increase in creatinine dosage and lipid peroxidation (TBARS) compared to the control group. In the period of 12 hours after APAP intoxication all parameters evaluated were altered; there was an increase of ALT, AST, and necrosis, besides the increase of redox status biomarkers as carbonylated protein, TBARS, and MMP-9. We also observed activation of the inflammasome pathway as well as a reduction in the regenerative capacity of hepatocytes with a decrease in binucleated liver cells. In cytochrome gene expression, the mRNA level increased in CYP2E1 isoenzyme and reduced CYP1A2 expression. This study indicated that early treatment is necessary to mitigate APAP-induced acute liver injury, and alternative therapies capable of controlling the progression of intoxication in the liver are needed.

Hepato-protective potentials of aqueous, chloroform and methanol leaf extracts of Whitfieldia lateritia on 2, 4-dinitrophenylhydrazine-induced anaemia in rats

This study aimed at investigating the hepato-protective potentials of the aqueous, chloroform and methanol leaf extracts of Whitfieldia lateritia on 2, 4-dinitrophenylhydrazine (2,4-DNPH)-induced anaemia in rats. The toxicity study, quantitative phytochemical screening, total and direct bilirubin concentrations, mean protein, albumin and globulin concentrations, as well as mean liver marker enzymes activities (ALT, AST and ALP) were carried out using standard procedures. Thirty-six wistar rats were grouped into six (n =6). Group I: normal control; Group II: negative control; Group III: administered 0.6 ml/kg body weight (b.w) of Astifer (standard Haematinic); Group IV to VI were administered 400 mg/kg b. w. of the aqueous, chloroform and methanol leaf extracts, respectively. Induction of anaemia was achieved in the test groups (II-VI) by administration of 2, 4-dinitrophenylhydrazine (20 mg/kg b.w.) once daily for seven days. Administration of extracts commenced subsequently and lasted for 21 days. Animals were sacrificed on the 22nd day and blood collected for laboratory analysis. ALT, AST and ALP activities of group II anaemic rats showed significant (P < 0.05) reduction compared with normal control rats. Group III rats showed significant (P < 0.05) increase in ALT, AST and ALP activities compared with group II anaemic rats. Group IV rats showed significant (P < 0.05) increase in ALT and AST activity compared with group III rats. The total bilirubin concentration of group II rats was non-significantly (P > 0.05) higher compared with the normal control rats. Groups IV and VI rats showed non-significant (P > 0.05) reduction in total bilirubin concentration compared with group V rats. In conclusion, W. lateritia leaf has beneficial hepato-protective properties in Wistar rats at therapeutic dose that supports its use in the treatment of hepatic diseases

Early clinical phenotype of late onset Pompe disease: Lessons learned from newborn screening.

Thoroughly phenotype children with late-onset Pompe disease (LOPD) diagnosed via newborn screening (NBS) to provide guidance for long-term follow up. Twenty infants ages 6-21 months with LOPD diagnosed by NBS underwent systematic clinical evaluation at Duke University including cardiac imaging, biomarker testing, physical therapy evaluation, and speech-language pathology evaluation. Of the 20 infants, four were homozygous for the "late-onset" IVS1 splice site variant c.-32-13 T > G, fourteen were compound heterozygous, and two did not have any copies of this variant. None of the patients had evidence of cardiomyopathy or cardiac rhythm disturbances. Biomarker testing showed an increase in CK, AST, and ALT in 8 patients (40%) and increase in Glc4 in two patients (10%). All patients demonstrated postural and kinematic concerns. Three patients (17%) scored below the 10%ile on the Alberta Infant Motor Scale (AIMS) and 15 patients (83%) scored above the 10%ile. Speech-language pathology assessments were normal in all patients and mild feeding/swallowing abnormalities were noted in nine patients (45%). Our data show high variability among children with LOPD diagnosed via NBS. Careful physical therapy evaluation is necessary to monitor for subtle musculoskeletal signs that may reflect early muscle involvement. Patients should be monitored closely for symptom progression.

Comparative Study between Pregnant and Non-Pregnant Women Regarding Variation of Liver Function Tests: Assessment of Health Literacy


 
 
 Context: Pregnancy is associated with normal physiological adaptive changes. Biochemical parameters reflect these changes and are distinct from the non-pregnant state. Low levels of health literacy have been shown to result in less healthy choices, riskier behavior, poorer health, less self-management, and more hospitalization among that category of adult patients. Aim: The study aimed to examine the effect of pregnancy on liver function tests among pregnant women during various trimesters of pregnancy and compare with non-pregnant and determine the patients' level of health literacy regarding the variation of liver function tests among those patients.
 Methods: A descriptive cross-sectional design was used to achieve the study aim. A random sample of 65 women was selected from an outpatient clinic in the maternity hospital; 54 out of them were pregnant women. Three tools were used to collect data, socio-demographic and clinical data assessment sheet; assessment of liver function tests by Cobas c 311; and health literacy management scale. Results: The sample's age range was between 20-40 years. This study revealed that; serum albumin levels decreased from the first trimester (3.7-4.7), and this decrease became progressively more accentuated as the pregnancy advanced (3.35-4.36 decreased significantly to 3.19-3.81). There was no significant decrease in serum AST between pregnant and non-pregnant women, but there was a significant decrease in ALT in pregnant women compared with non-pregnant women (11.90 Vs. 8.60 at p 0.017). In the current study, Serum alkaline phosphatase (ALP) was significantly higher (P˂0.0001) during the third trimester (63-171) compared with the second trimester (33-137), and the first trimester (36-129), and with the control group (48-122). Finally, it was found that a significant decrease in total serum bilirubin concentrations during the second (0.11-0.38) and third trimesters (0.12-0.42) compared to control (0.11-1.57) and the first trimester (0.12-0.85). Moreover, most of the studied sample has a low level of health literacy for all subscales and the total scores.
 Conclusion: During normal pregnancy, most values of liver function tests remain below the normal upper limits compared to non-pregnant women. Any increase in serum ALT and AST activity levels and serum bilirubin should be considered pathologic and prompt for further evaluation. Moreover, most of the studied sample has a low level of health literacy for all subscales and the total scores. The study recommended that the liver function tests should be routinely investigated during pregnancy to outline any pathologic changes. Focusing on the nurse's role, she should emphasize increasing the patient's level of health literacy regarding the variation of liver function tests. So, it is a must for nurses to develop many skills to enable them to function for this category of patients with low health literacy levels. Also, those patients should be equipped with information-seeking behavior, decision-making abilities, and problem-solving approaches along their health and illness continuum.
 
 

Abstract P1-17-10: H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer - A phase II study

Abstract Purpose: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both and wild-type and mutant ERα by targeting cysteine 530 and enforcing antagonist conformation. H3B-6545 demonstrated preclinical high activity in breast cancer models with constitutively active ESR1 mutations (Furman C, SABCS 2020) and clinical activity in pretreated women with ER+ breast cancer (Hamilton EP, ASCO 2021). Patients and Methods: The primary objective of the phase II is to estimate the objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and secondary objectives include safety. Results: 94 pts were treated with 450 mg daily, the recommended phase II dose: 11 in the phase I and 83 in the phase II parts of the trial. Patients and tumor characteristics were presented previously (Hamilton EP, ASCO, 2021). As of March 31, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), nausea (17%), fatigue (16%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (39%), hemoglobin decrease (38%), Lymphocytes decrease (37%), ALT increase (14%), AST increase (13%), bilirubin increase (12%), and creatinine increase (12%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 35% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in Table 1. CI: Confidence interval. N: total number of pts in full analysis set, used in PFS analysis. n: number of response-evaluable pts, used in ORR and CBR analysis. Efficacy estimates were consistent across the various subgroups. Responses were demonstrated in heavily pretreated pts, pts with visceral metastases, pts with constitutionally active ESR1 Y537S mutations, and in pts who received chemotherapy in the metastatic setting. Numerically higher response rate and longer PFS were observed in pts with ESR1 Y537s. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was consistent across the various subgroups. Tumors harboring the constitutionally active ESR1 Y537S mutation may present higher ERα activity, and consequently enrich for luminal A traits and demonstrate greater lineage dependence on ERα. Table 1.Consistency of H3B-6545 activity across the key subgroupsEfficacyClinical CharacteristicORR % (95% CI)CBR % (95% CI)Median PFS mo (95% CI)Overall population (N=94, n=72)16.7 (8.9, 27.3)40.3 (28.9, 52.5)5.1 (3.2, 6.2)Liver and/or lung metastases (N=76, n=62)17.7 (9.2, 29.5)41.9 (29.5, 55.2)5.4 (1.8, 7.2)≥3 prior regimens (N=49, n=39)20.5 (9.3, 36.5)48.7 (32.4, 65.2)5.4 (3.5, 7.3)Prior chemotherapy (N=47, n=35)17.1 (6.6, 33.6)51.4 (34.0, 68.6)5.5 (3.6, 7.3)PgR+ (N=38, n=32)15.6 (5.3, 32.8)50.0 (31.9, 68.1)5.4 (2.0, 8.8)ESR1 clonal Y537S (N=10, n=10)30.0 (6.7, 65.2)60.0 (26.2, 87.8)7.3 (0.8, 11.2)ESR1 clonal D538G (N=19, n=17)0.0 (0.0, 19.5)35.3 (14.2, 61.7)5.4 (1.7, 7.2) Citation Format: Erika P Hamilton, Judy S Wang, Timothy Pluard, Aki Morikawa, E Claire Dees, Robert H Jones, Barbara Haley, Anne Armstrong, Adam L Cohen, Pamela Munster, Gail S Wright, Fadi Kayali, Lisa Cantagallo, Manav Korpal, Jenny Long, Jianjun Xiao, Benoit Destenaves, Lei Gao, Tarek Sahmoud, Antonio Gualberto, Dejan Juric. H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer - A phase II study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-10.

HBV Reactivation in Patients with Past Infection Affected by Non-Hodgkin Lymphoma and Treated with Anti-CD20 Antibody Based Immuno-Chemotherapy: A Multicenter Experience.

Hepatitis B virus reactivation (HBVr) can develop in HBV surface antigen (HBsAg) positive or HBsAg-negative and anti-hepatitis B core antigen antibodies (anti-HBc) positive (past HBV infection) patients receiving immuno-chemotherapy for hematological malignancies. A higher rate of HBVr is associated with the use of rituximab (R) in patients with past HBV infection, thus justifying an antiviral prophylaxis. In this study we evaluated the incidence of HBVr in a real-life cohort of 362 anti-HBc-positive subjects affected by non-Hodgkin lymphoma (NHL), mainly receiving lamivudine (LAM) prophylaxis (93%) and all undergoing a R-containing regimen. A retrospective, multicenter, observational study was conducted in 4 Italian Hematology Departments. The primary endpoint was the incidence of virologic (HBV DNA-positive), serologic (HBsAg-positive) and clinical (ALT increase > 3 × upper limit of normal) HBVr, which occurred in five, four and one patients, respectively, with a total HBVr rate of 1.4%. None of them had to discontinue the chemotherapy program, while two patients required a delay. Treatment-related adverse events (AEs) were reported during LAM prophylaxis in three patients (0.9%). In conclusion, this study confirms the efficacy and safety of LAM prophylaxis in anti-HBc-positive patients undergoing R-containing regimens.

​Pathomorphological, Haemato-biochemical and Diagnostic Imaging Studies in Canine Pyometra

Background: Pyometra is the most common genital affections observed in bitches around the globe in-spite of advancement of disease diagnosis and treatment. Paucity of available literature regarding pyometra in canines in Odisha prompted to undertake an in-depth analysis on determinants linked to epidemiology, haemato-biochemical, clinicopathological and diagnostic imaging in pyometra bitches. Methods: During the period 2019-20, a total of 148 bitches were screened for canine pyometra in and around Bhubaneswar, Odisha on the basis of clinical signs, haematology and diagnostic imaging. Uterus was collected after ovario-hysterectomy and processed for histopathology through routine haematoxylin and eosin staining. Result: The overall incidence of pyometra was 15.54% with 4% mortality rate. Present study recorded a significant higher occurrence of pyometra in older bitches ( greater than 7 year, 78.26%), smaller breeds like Spitz (47.82%), nulliparous bitches (60.86%) and dogs in dioestrus stage (82.60%). Haematological examinations revealed anaemia with marked leucocytosis and neutrophilia. There was significant increase in AST, ALT, ALP and BUN concentrations in affected bitches. Enlarged uterus with hypo echoic tubular structures containing mostly echogenic fluids were constant findings through ultrasonography. Flabby uterine horns with thick and corrugated endometrial wall containing profuse mucopurulent exudates were seen during necropsy. Chronic inflammatory response leading to intense haemorrhages and hyperaemia were constant microscopic changes. The most common isolated pathogen in canine pyometra was Escherechia coli (67.5%).