Increased Alanine Aminotransferase Research Articles

Novel triazole derivatives as potential rodenticides against the Norway rat, R. norvegicus: histology, biochemical alternations, and field application

Economically speaking, rodents possess a serious threat to the agriculture sector. One of these organisms that directly threaten agriculture, stocks, and others is the Norway rat, Rattus norvegicus (R. norvegicus). The 2-cyano-N-(1H-1,2,4-triazol-3-yl) acetamide (1) was used as a precursor to give 2-cyano-3-(dimethylamino)-N-(1H-1,2,4-triazol-3-yl) acrylamide (2) and ethyl 2-amino-5-cyano-1,6-dihydro-6-oxo-1-(1H-1,2,4-triazol-3-yl) pyridine-3-carboxylate (3). Infra-red, 1H-NMR, 13C-NMR, MS, and elemental analysis were done for the precise structure elucidation of the applied synthons. The prepared compounds were tested as potential rodenticides against the Norway rat, Rattus norvegicus. Toxicity analysis using four serial doses of both prepared compounds revealed that the LD50 values were 160.6 and 391.7 mg/kg body weight, for ethyl 2-amino-5-cyano-1,6-dihydro-6-oxo-1-(1H-1,2,4-triazol-3-yl) pyridine-3-carboxylate (3) and 2-cyano-N-(1H-1,2,4-triazol-3-yl) acetamide (1), respectively. Several biological variables, such as alanine transaminase (ALT), aspartate transaminase (AST), serum urea, creatinine, and total protein, have been assessed and evaluated as biological response indicators. Analysis revealed a highly significant increase in both AST, ALT, urea, and creatinine levels, while the total protein level showed a considerable reduction in treated rats exposed to 2-cyano-N-(1H-1,2,4-triazol-3-yl) acetamide (1) and ethyl 2-amino-5-cyano-1,6-dihydro-6-oxo-1-(1H-1,2,4-triazol-3-yl) pyridine-3-carboxylate (3) when compared to the control treatment. Liver histological examination showed structural changes in the form of congestion in the central vein, necrosis in some hepatic regions, and pyknotic nuclei, while kidney histological examination showed vacuolar degeneration of the epithelial cells of some convoluted tubules and the disappearance of some glomeruli and other marked atrophies. Necrosis in some areas was noticed. Field application through bait consumption took place with a satisfactory reduction of 68.4% for ethyl 2-amino-5-cyano-1,6-dihydro-6-oxo-1-(1H-1,2,4-triazol-3-yl) pyridine-3-carboxylate (3), while it was 61.9% for 2-cyano-N-(1H-1,2,4-triazol-3-yl) acetamide (1) when compared to the recommended Zinc phosphide commercial rodenticide that poses an 81% reduction.Graphic abstract

Effect of COVID-19 on Liver Enzymes in Hospitalized COVID-19 Patients in the Gaza Strip: A Retrospective Study

In severe cases, the novel coronavirus disease 2019 (COVID-19) can cause respiratory failure and multiple organ dysfunction, including liver injury. This study assessed the COVID-19 effect on liver function among hospitalized COVID-19 patients. Three-hundred and seventy patients were recruited. Patients were distributed as the following: control group (n=100), intensive care unit (ICU) hospitalized COVID-19 patients (n=140), and non-ICU hospitalized COVID-19 group (n=130). Data about the levels of liver enzymes were collected from the hospital medical records of the participants. Our results showed a significant increase in alanine aminotransferase (ALT) levels among the ICU hospitalized COVID-19 patients compared with the non-ICU hospitalized COVID-19 patients (p-value <0.01) and the controls (p-value <0.001). Aspartate aminotransferase (AST) concentration significantly increased among the ICU-hospitalized COVID-19 group compared with the non-ICU hospitalized COVID-19 group (p-value <0.01) and the controls (p-value <0.05). The ICU-hospitalized COVID-19 patients had a higher increase in alkaline phosphatase (ALP) levels compared to the non-ICU hospitalized COVID-19 patients and controls (p values <0.001). Based on ALT, AST, and ALP levels, we found that 73 (52%), 77 (55%), and 38 (27%) of the ICU hospitalized COVID-19 patients developed a liver injury. Of those, 12 (8.5%) died compared to 5 (3.5%) patients with abnormal liver function. In conclusion, these findings suggest that COVID-19 disease is associated with abnormal liver function and liver injury.

Small bowel intussusception after Roux-en-Y gastric bypass: A case report

Introduction: Small bowel intussusception after Rouxen-Y gastric bypass is a rare condition, with a reported incidence of 0.07–0.6%, and a multifactorial etiology. The severity of the condition ranges from small bowel edema to ischemia and perforation with peritonitis, and the clinical presentation and blood tests are non-specific. The computed tomography (CT) scan is the best diagnostic tool in an emergency department context. Case Report: The authors present the case of a 41-year-old male patient, with history of Roux-en-Y gastric bypass two years before, who presented in the emergency department with acute onset abdominal pain and nausea. Abdominal exploration showed a tender mass in the left upper quadrant. Blood tests showed an increase in alanine transaminase (ALT) and aspartate transaminase (AST) and abdominal CT scan was compatible with a small bowel intussusception, without other findings. A diagnostic laparoscopy confirmed the diagnosis, and the intussusception was resolved without need of bowel resection. The patient showed no complications in the immediate post-operative period, with clinical and analytical improvement, and was discharged on the sixth post-operative day, without relevant complaints in the follow-up appointments. Conclusion: Due to the non-specific clinical presentation of small bowel intussusception, it is required a high level of suspicion in patients who underwent gastric bypass and present with abdominal pain. In terms of surgical approach, resolution of the intussusception may be enough in many cases, when there is no vascular compromise of the bowel, while the evidence of ischemia requires bowel resection.

Synthesis of Methylgenipin and Evaluation of Its Anti-Hepatic Injury Activity.

Genipin has been the focus of research as a multifunctional compound for the treatment of pathogenic diseases. However, hepatotoxicity caused by oral genipin raises concerns about its safety. To obtain novel derivatives with low toxicity and efficacy, we synthesized methylgenipin (MG), a new compound, using structural modification, and investigated the safety of MG administration. The results showed that the LD50 of oral MG was higher than 1000 mg/kg, no mice died or were poisoned during the experiment in the treatment group, and there was no significant difference in biochemical parameters and liver pathological sections compared with the control. Importantly, MG (100 mg/kg/d) treatment for 7 days reduced alpha-naphthylisothiocyanate (ANIT)-induced increases in liver index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), and total bilirubin (TBIL) levels. Histopathology demonstrated that MG could treat ANIT-induced cholestasis. In addition, using proteomics to investigate the molecular mechanism of MG in the treatment of a liver injury may be related to enhancing antioxidant function. Kit validation showed that ANIT induced an increase in malondialdehyde (MDA) and a decrease in superoxide dismutase (SOD) and glutathione (GSH) levels, while the MG pretreatments, both of which were significantly reversed to some extent, suggested that MG may alleviate ANIT-induced hepatotoxicity by enhancing endogenous antioxidant enzymes and inhibiting oxidative stress injury. In this study, we demonstrate that the treatment of mice with MG does not cause impaired liver function and provide an investigation of the efficacy of MG against ANIT-induced hepatotoxicity, laying the foundation for the safety evaluation and clinical application of MG.

Ribociclib-induced visual hallucination in a patient with metastatic breast cancer.

Cyclin-dependent kinase (CDK) 4/6 inhibitors are widely used in combination with aromatase inhibitors or fulvestrant for the treatment of locally advanced or metastatic hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) breast cancer. Hematological toxicities (e.g. neutropenia, thrombocytopenia, anemia, lymphopenia, or febrile neutropenia), infections, decreased appetite, exhaustion, headache, dizziness, cough, nausea, vomiting, diarrhea, alopecia, rash, increased alanine aminotransferase and aspartate aminotransferase levels, and QT interval prolongation are frequent side effects associated with the use of CDK 4/6 inhibitors. However, to our knowledge, no case of hallucination associated with CDK 4/6 inhibitor use has been described in the English-language literature. We report a case of a 72-year-old woman with metastatic breast cancer who developed visual hallucinations after receiving ribociclib, a CDK 4/6 inhibitor, and letrozole for 3 days. Cranial imaging and blood tests did not reveal the cause of the hallucinations. The visual hallucinations completely resolved within 4 days after the ribociclib treatment was terminated. The patient received only letrozole for 2 weeks, and ribociclib treatment was restarted 2 weeks later. Visual hallucinations recurred on the third day of treatment, and ribociclib treatment was discontinued again. The patient recovered completely from visual hallucinations 4 days after discontinuation. Subsequently, treatment was continued with letrozole and palbociclib, another CDK 4/6 inhibitor. Hallucinations did not recur during follow-up. To our knowledge, this is the first reported case of hallucinations caused by ribociclib; notably, it shows that symptoms may develop in the early stage of treatment.

Effect of alpha-lipoic acid and caffeine-loaded chitosan nanoparticles on obesity and its complications in liver and kidney in rats

The present work investigated the effect of α-lipoic acid (ALA) and caffeine-loaded chitosan nanoparticles (CAF-CS NPs) on obesity and its hepatic and renal complications in rats. Rats were divided into control, rat model of obesity induced by high fat diet (HFD), and obese rats treated with ALA and/or CAF-CS NPs. At the end of the experiment, the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) and the levels of urea, creatinine, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were determined in the sera of animals. In addition, malondialdehyde (MDA), nitric oxide (NO), and reduced glutathione (GSH) were measured in hepatic and renal tissues. Renal Na+, K+-ATPase was assessed. The histopathological changes were examined in the hepatic and renal tissues. Obese rats showed a significant increase in AST, ALT, ALP, urea, and creatinine. This was associated with a significant increase in IL-1β, TNF-α, MDA, and NO. A significant decrease in hepatic and renal GSH and renal Na+, K+-ATPase activity was recorded in obese rats. Obese rats also showed histopathological alterations in hepatic and renal tissues. Treatment with ALA and/or CAF-CS NPs reduced the weight of obese rats and ameliorated almost all the hepatic and renal biochemical and histopathological changes induced in obese rats. In conclusion, the present findings indicate that ALA and/or CAF-CS NPs offered an effective therapy against obesity induced by HFD and its hepatic and renal complications. The therapeutic effect of ALA and CAF-CS NPs could be mediated through their antioxidant and anti-inflammatory properties.

Early drug-induced hepatotoxicity in newly diagnosed HIV-positive patients on ARV therapy: A retrospective follow-up study of liver function profiles

Antiretroviral therapy (ART) is a primary therapeutic modality for managing individuals with Human Immunodeficiency Virus (HIV) infection, and its efficacy has been established. However, the safety profiles of ART need to be continually monitored, including early elevated liver function test (LFT) after antiretroviral (ARV) initiation. This study aimed to assess the incidence of abnormal LFT among HIV-positive patients receiving initial ARV and to identify factors associated with abnormal LFT. A retrospective cohort study without a control group summarised medical records from Dr Sardjito General Hospital, Yogyakarta between January 2014 and December 2021. The study subjects were adult HIV patients taking their first ARV and underwent follow-up visits for at least two weeks. Study outcomes were LFT levels, abnormal LFT, and factors associated with abnormal LFT during follow-up visits at 2 wk, 6 mo, and 12 mo. Univariate and multivariate analyses will be performed with a significance level of p<0.05. A total of 137 subjects with 203 visits were retrieved from medical records. The subjects' mean age was 33.4 years, predominantly male, younger, unmarried, in the early stage of HIV infection, and without comorbidities. The findings showed a significant increase in alanine transaminase (ALT) at all three follow-up visits: 2 wk (p=0.02), 6 mo (p=0.003), 12 mo (p=0.001) and an increase in aspartate aminotransferase (AST) after 6 mo (p=0.007) and 12 mo (p=0.04). Abnormal LFT levels (AST and/or ALT) were observed in 23.4% of patients after a normal baseline, with ALT increase being more common. Furthermore, homosexuality was identified as a significant independent factor associated with abnormal LFT (AOR=3.1; 95% CI 1.27-7.51; p=0.01). The findings indicate exceptionally elevated LFT levels and the occurrence of abnormal LFTs among HIV-positive patients initiating ARVs. The increase in abnormal LFTs was significantly associated with patients identifying as homosexual, where hepatitis co-infection may be a contributing factor. The limited study design and measured variables warrant further investigation.

A first-in-human phase I, dose-escalation and dose-expansion study of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET positive solid tumors.

9111 Background: RET gene fusions have been identified as oncogenic drivers in 1-2% of non-small-cell lung cancer (NSCLC) and 10-20% of papillary thyroid carcinomas. Activating RET mutations occur in 50-60% of medullary thyroid cancer (MTC). Recently, selective RET TKIs, selpercatinib and pralsetinib, were approved for RET positive solid tumors by FDA. SY-5007 is a highly potent RET inhibitor that selectively targets RET fusions and mutations. This study is to investigate the safety, PK characteristics and preliminary efficacy of SY-5007 in Chinese patients with advanced RET-altered solid tumors. Methods: In this first-in-human phase I study, eligible patients previously treated and with positive RET were enrolled. In the dose escalation phase, following 3+3 design, the patients were administered orally with SY-5007 20 mg once daily, or 20, 40, 80, 120, 160, 200 mg twice daily in a 28-day cycle. The expansion doses (160 and 200 mg twice daily) were executed in a dose expansion phase to determine a recommended phase II dose (RP2D). Then three cohorts ( RET fusion-positive NSCLC or thyroid cancers and RET mutant MTC) at RP2D were expanded in eligible patients. Primary endpoints included safety, tolerability, MTD, DLTs. Secondary endpoints included PK and preliminary antitumor activity of SY-5007 per RECIST v1.1. Results: As of Feb.06, 2023, a total of 60 patients including 55 RET fusion NSCLC and 5 RET mutant solid tumors were enrolled into dose escalation cohorts (n = 17) and dose expansion cohorts (n = 43).Totally, 55 (91.7%) patients experienced treatment-related adverse events (TRAEs) including increased aspartate aminotransferase (50.0%), increased alanine aminotransferase (41.7%), diarrhea (41.7%), etc. Grade ≥3 TRAEs were observed in 22 (36.7%) patients including hypertension (15%), diarrhea (5%), increased alanine aminotransferase (3.3%), etc. PK study showed SY-5007 was absorbed rapidly, exposure of SY-5007 increased in a dose-dependent manner at doses between 20 and 160 mg twice daily, and it was saturated at 160 mg twice daily. In 50 evaluable patients, the overall ORR and DCR was 62.0% (95% CI, 47.2-75.4) and 94.0 % (95% CI, 83.5-98.8), respectively. 29 patients (24 NSCLC, 4 MTC) received SY-5007 at 160 mg twice daily, 27 of 28 (96.4%) evaluable patients showed tumor regression, ORR and DCR was 72.4% (95% CI, 52.8-87.3) and 89.7% (95% CI, 72.7-97.8), respectively. For NSCLC patients, the ORR and DCR was 75.0% (95% CI, 53.3-90.2) and 91.7% (95% CI, 73.0-99.0), respectively. Conclusions: SY-5007 was well tolerated in patients. Preliminary antitumor activity was also observed in patients with advanced RET-fusion positive NSCLS and RET mutant MTC. The pivotal Phase II clinical study of SY-5007 in NSCLC patients is ongoing. Research Sponsor: Shouyao Holdings (Beijing) Co., Ltd. Clinical trial information: NCT05278364 .

First-in-human study of ZG005, a dual specific antibody targeting TIGIT and PD-1, as monotherapy in patients with advanced solid tumors.

e14504 Background: Multiple groups have shown that TIGIT contributes to immune-tolerance by inhibiting immune responses mediated by T cells and NK cells through binding its ligand, CD155 (PVR), on antigen-presenting cells and a variety of non-hematopoietic cell types including tumor cells. ZG005, a PD-1 and TIGIT dual specific antibody, is a promising immunotherapy for tumors as blocking these two pathways could synergistically activate T cells and enhance the anti-tumor activity of NK cells. We have conducted a Phase 1 clinical study to assess the tolerability, safety, preliminary efficacy of this drug. Methods: During the dose escalation stage, an accelerated titration design (ATD) in the first dose and the standard "3+3" design in the rest doses were used. Subjects were patients with advanced solid tumors who failed to the available standard treatments. The dose groups were set from 0.3 to 20 (0.3, 1, 3, 10, 20) mg/kg, intravenous infusion, once every 3 weeks. The first 21-day-period was defined as the dose-limiting toxicity (DLT) observation period. Subjects could continue to receive ZG005 until treatment discontinuation criteria were met. Tumor response was assessed by RECIST1.1 and iRECIST. Pharmacokinetics and receptor occupancy (RO) profiles were also assessed in this study. Results: A total of 16 subjects (6 males and 10 females) completed the DLT observation, with median age of 59 years. Nine (56.3%) of them received at least 3 lines of antineoplastic therapies, and six (31.6%) have been exposed to PD-1 or PD-L1 inhibitors. There was one DLT event found in the 1 mg/kg dose group, showing a grade 3 hepatic function abnormal (immune-mediated). No other DLT event was observed. Forty-nine treatment-related adverse events (TRAEs) including the aforementioned DLT event occurred. TRAEs were basically grade 1 or 2, except one female who suffered from rectal cancer unfortunately died at home. Due to limited information gathered, the investigators considered that the death was mostly related to the underlying condition, but the cause of the study drug could not be completely excluded. The most frequent TRAEs were increases in alanine aminotransferase, lipase, blood creatine phosphokinase MB, blood alkaline phosphatase and blood lactate dehydrogenase, with an incidence of 18.8% (3/16). Of the 10 evaluable cases, 1 had PR, 6 had SD and 3 had PD. The longest duration of administration was in a subject with intrahepatic cholangiocarcinoma who received 9 cycles and is still remaining in this study. The Cmax and AUC increased from 0.3-20 mg/kg approximately in dose proportion. Complete and sustained RO of T cells in PBMCs was observed at ≥ 3 mg/kg doses of ZG005 for at least 3 weeks. Conclusions: ZG005 demonstrates good safety and tolerance in this escalation study. It also demonstrates preliminary antitumor effects in patients with solid tumors, a good PK profile and long-lasting RO. Clinical trial information: ChiCTR20220021 .

Larotrectinib long-term efficacy and safety in adult patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer.

3141 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in a broad array of tumor types. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pts with TRK fusion cancer based on a rapid, robust, and durable objective response rate (ORR) in both adult and pediatric pts with various non-primary CNS cancers. Here, we report data on an expanded cohort of adult pts with TRK fusion cancer treated with larotrectinib. Methods: Adults with non-primary CNS TRK fusion cancer treated in three larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687) were included. Larotrectinib was administered at 100 mg twice daily in most pts. Responses were assessed per Independent Review Committee (IRC) using RECIST v1.1. Data cut-off: July 2022. Results: As of July 2022, there were 194 adult pts enrolled, with 180 eligible for efficacy analyses by IRC; 22 pts had known brain metastases at baseline. There were 24 different tumor types; the most common were lung (n=30; 15%), soft tissue sarcoma (n=30; 15%), thyroid (n=28; 14%), salivary gland (n=25; 13%), and colon (n=23; 12%). Median age was 57 years (range 19–90). The gene fusions involved NTRK1 (n=90; 46%), NTRK2 (n=7; 4%), or NTRK3 (n=97; 50%). Pts had previously received a median of one systemic therapy (range 0–10). ORR was 57% (95% CI 50–65): 29 (16%) complete response (including one pathological complete response), 74 (41%) partial response, 39 (22%) stable disease, 23 (13%) progressive disease, and 15 (8%) not evaluable. ORR in 22 evaluable pts with baseline CNS metastases was 68% (95% CI 45–86). Median time to response was 1.8 months, and median duration of response was 43.3 months (95% CI 29.2–not estimable [NE]) at a median follow-up of 32.3 months. Median progression-free survival was 24.6 months (95% CI 11.3–34.5) at a median follow-up of 28.5 months. Median overall survival was 48.7 months (95% CI 38.5–NE) at a median follow-up of 33.8 months. At data cut-off, 39 of the 73 pts who had disease progression continued treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs occurred in 27 (14%) pts. Treatment discontinuation due to TRAEs was reported in one pt (increased alanine aminotransferase and aspartate aminotransferase). Conclusions: In this expanded dataset with extended follow-up, larotrectinib continues to demonstrate rapid and durable responses, extended survival, and a favorable safety profile in adults with TRK fusion cancer, including those with CNS metastases. These results support the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing pts with solid tumors; this ensures that pts are offered the right medicine for their disease as soon as possible. Clinical trial information: NCT02576431 , NCT02122913 , NCT02637687 .

Camrelizumab in combination with apatinib as a perioperative treatment for patients with hepatocellular carcinoma at high risk of recurrence: A prospective, single-arm, phase 2 study.

4120 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and a rising cause of cancer-related mortality. To date, the optimal perioperative treatment strategy for HCC patients remains unclear. It is urgent to develop novel and reliable therapeutic interventions to reduce the risk of recurrence and improve survival in patients with locally advanced HCC. Methods: This prospective, exploratory, single-arm, phase 2 study enrolled patients with primary resectable HCC who had not received prior systemic therapy. Before surgery, patients received combination treatment with four cycles of camrelizumab (200 mg, Q2W) plus apatinib (250 mg, QD). Each cycle was two weeks. The feasibility of hepatic resection was assessed by radiographic imaging. After 4-8 weeks of surgery, patients continued combination therapy (camrelizumab [200 mg, Q2W] and apatinib [250 mg, QD]) for one year. Primary endpoint was major pathological response (MPR). Secondary endpoints were pathologic complete response rate (pCR), objective response rate (ORR), disease-free survival (DFS), and safety. Exploratory endpoint was microvascular invasion (MVI). This study is registered on Clinical Trials.gov, number NCT04701060. Results: Between Jan 12, 2021, and Aug 17, 2022, 31 patients with a median age of 54 years were enrolled. Among these, 21 patients (67.7%) had hepatitis B virus infection. Before surgical incision, two patients withdrew informed consent. Therefore, ORR based on RECIST 1.1 and mRECIST were 13.8% (4/29) and 48.3% (14/29), respectively. 26 patients underwent hepatic resection, R0 resection rate was 100%, 10 (38.5%) patients achieved MPR, and pCR rate was 7.7%. The reasons for patients not undergoing surgery were disease progression and serious adverse events (AEs). Among patients with MVI, M0 was found in 57.7% (15/26) patients, MI was found in 34.6% (9/26) patients, and M2 was found in 7.7% (2/26) patients. 1-year DFS rate was 77.4%, and median DFS was not reached. The most common AEs included increased aspartate aminotransferase (74.2%), increased alanine aminotransferase (70.1%), decreased platelet count (61.3%), anemia (58.1%), and decreased lymphocyte count (51.6%). Grade 4 AEs occurred in 7 of 31 patients, and there were no treatment-related deaths. Conclusions: Camrelizumab plus apatinib as a perioperative treatment is effective and tolerable in patients with HCC at high risk of recurrence. Preoperative neoadjuvant therapy has reduced the rate of MVI. Because of the short follow-up period, whether perioperative treatment can effectively reduce recurrence rates and improve long-term survival still needs further investigation. Clinical trial information: NCT04701060 .

Final analysis of the phase IB part of the LOC-R01 trial, a non-comparative randomized phase IB/II study of escalating doses of lenalidomide and ibrutinib in association with R-MPV for patients with a newly diagnosed primary central nervous system lymphoma (PCNSL).

7566 Background: Results of conventional induction chemotherapies in PCNSL need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results in the relapse setting, supporting to further assess their combination with standard high-dose methotrexate-based chemotherapy. Methods: Patients (pts) with newly diagnosed PCNSL, aged 18 to 60, were randomized to receive four 28-day cycles of either ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3+3 design for ibrutinib 420/560/280 mg (D3 to D14 and D17 to D28) and lenalidomide 20 mg D1 to 14/20 mg D1 to 21/15 mg D1 to 21. Responder pts then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. We present the results of the phase IB, including the toxicities that occurred throughout induction therapy. Results: 26 pts (median age 52) were randomized, 13 in each treatment group. Four DLTs (/21 evaluable pts) have been observed: grade 5 aspergillosis and pneumocystosis (N=1, ibrutinib 560 mg and concurrent high-dose corticosteroids without prophylaxis), grade 4 catheter-related infection > 7 days (N=1, lenalidomide 20 mg D1-14) and grade 3 increased alanine aminotransferase > 7 days (N=1, lenalidomide 20 mg D1-14 and N=1, lenalidomide 15 mg D1-21). RP2D of ibrutinib and lenalidomide were 560 mg (D3-14 and D17-28) and 15 mg (D1-21) respectively, in combination with R-MPV. One Lyell’s syndrome was reported as a serious adverse event (AE) at cycle 2 in the lenalidomide arm. Grade ≥3 treatment-related AEs occurring in ≥2 pts at any time during induction treatment are detailed in the table. After 4 induction cycles, 3/11 evaluable pts had CR/CRu and 7/11 had partial response (PR) in the ibrutinib group. In the lenalidomide arm, 6/10 evaluable pts had CR/CRu and 4/10 had PR. Survivals will be presented. Conclusions: Targeted induction immunochemotherapy with ibrutinib or lenalidomide and R-MPV is feasible for newly diagnosed PCNSL and shows promising response rates. Adverse events should be monitored carefully. The phase II part of the study is ongoing and opened to patients up to 65 years old. Clinical trial information: NCT04446962 . [Table: see text]

Safety and efficacy of D-1553 in KRAS G12C-mutated colorectal cancer: Results from a phase I/II study.

3563 Background: KRAS G12C mutation is an oncogenic driver that occurs in 3-4% of colorectal cancer (CRC). D-1553 is a novel oral and potent KRASG12C inhibitor. This phase I/II open-label study (NCT04585035) is an international multicohort study evaluating the safety, tolerability, pharmacokinetics (PK) and efficacy of D-1553 in patients (pts) with KRAS G12C mutated locally advanced or metastatic solid tumors. The Phase I part was conducted to determine the recommended phase 2 dose (RP2D) of D-1553. The Phase II part enrolled multiple expansion cohorts of different cancer types. The endpoints of the study include clinical activity, safety and PK. Here we report preliminary data from pts with locally advanced unresectable or metastatic CRC receiving ≥ RP2D of D-1553 monotherapy. Methods: Pts with locally advanced unresectable or metastatic CRC with progression after standard treatment were enrolled in the Phase I and Phase II parts of the study. Pts were required to have KRAS G12C mutations in tumor or ctDNA samples and no prior KRAS G12C directed therapy. The current analysis includes CRC patients who were treated with D-1553 at RP2D (600 mg BID in Phase I and II) and above (800 mg BID in Phase I) as monotherapy. Results: As of 30 December 2022, 24 pts with previously heavily treated locally advanced or metastatic CRC (54.2% male; median age, 61.5 years [range 44, 74]; ECOG PS 0/1: 45.8%/54.2%) were enrolled and received D-1553 600 mg (n = 23) or 800 mg (n = 1) BID monotherapy. 95.8% of pts had stage IV disease. 66.7% had ≥ 2 prior lines of therapy (median: 2 [range, 1, 6]). Median treatment duration was 5.75 (range 1.51, 11.83) months (mo) with a median follow-up of 6.64 (range 2.46, 13.11) mo. Confirmed ORR was 20.8% (5/24) (95% CI: 7.1%-42.2%), and DCR was 95.8% (23/24). Median PFS was 7.62 mo (95% CI, 2.89 to 9.53 mo). At the data cutoff date, 37.5% (9/24) of pts remain on study treatment. Treatment-related adverse events (TRAEs) of any grade occurred in 50% (12/24), most were grade 1 or 2 in severity. Two pts had grade 3/4 TRAEs (alanine aminotransferase increased, diarrhea, hypertension and hypokalaemia). No TRAEs were fatal or resulted in D-1553 discontinuation. The most common (≥ 5%) TRAEs (any grade) were increased alanine aminotransferase or aspartate aminotransferase, increased total bilirubin or conjugated bilirubin, diarrhea, hypothyroidism and nausea. Conclusions: D-1553 demonstrated a tolerable safety profile and promising monotherapy activity in pts with heavily pretreated locally advanced or metastatic CRC and KRAS G12C mutations. This study is ongoing to further evaluate the safety and efficacy of D-1533 as monotherapy and in combination with cetuximab or chemotherapy in pts with locally advanced or metastatic CRC. Clinical trial information: NCT04585035 .

Camrelizumab in combination with doxorubicin, cisplatin, ifosfamide, and methotrexate as neoadjuvant therapy for osteosarcoma: A single-arm, exploratory phase II trial.

11526 Background: Tumor necrosis rate after neoadjuvant therapy is one of the strongest predictors of long-term outcome for patients with osteosarcoma. Patients with good response (tumor necrosis rate ≥90%) have a substantially better survival than those with poor response (tumor necrosis rate < 90%), with 5-year overall survival of 75-80% and 55-65%, respectively. However, treatments for osteosarcoma have not yet shown much progress since the introduction of perioperative chemotherapy in 1970s. New neoadjuvant combinations are required to explored for osteosarcoma. Methods: In this phase II trial (NCT04294511), patients aged 14-65 years with histopathologically confirmed osteosarcoma and Eastern Cooperative Oncology Group performance status of 0-1 received three 21-day cycles of neoadjuvant regimen (camrelizumab 200 mg on day 1 of each cycle; doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 1-2 of cycles 1 and 3; cisplatin 100 mg/m2 on day 2 of cycles 1 and 3; methotrexate 8-12 g/m2 on day 12 of cycle 1; and ifosfamide 3 g/m2 on days 1-4 of cycle 2). Surgery was scheduled 12-14 days after neoadjuvant therapy. Two weeks after surgery, patients received 6 cycles of adjuvant therapy (camrelizumab 200 mg on day 1 of each cycle; doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 9-10 of cycles 1, 3, and 5; cisplatin 100 mg/m2 on day 10 of cycles 1, 3, and 5; methotrexate 8-12 g/m2 on day 2 of cycles 1, 3, and 5; and ifosfamide 3 g/m2 on days 1-4 of cycles 2, 4, and 6). The primary endpoint was good response (tumor necrosis rate ≥90%) rate after neoadjuvant therapy. Results: A total of 86 patients were screened and 75 patients signed informed consent from December 2019 to June 2022. By the data cutoff date on December, 2022, 8 patients did not complete neoadjuvant therapy and 2 patients refused surgery. 65 patients completed neoadjuvant therapy, one patient had disease progression before surgery, 64 received surgical resection and adjuvant therapy, and 44 completed adjuvant therapy. Thirty-one (48.4%, 95%CI: 36.6%-60.4%) of 64 patients showed good response. The most common grade 3-4 adverse events were decreased platelet count (44.0%), decreased white blood cell (37.3%), decreased neutrophil count (29.3%), oral mucositis (14.7%), increased alanine aminotransferase (12.0%), and increased aspartate aminotransferase (10.7%). Conclusions: Camrelizumab combined with doxorubicin, cisplatin, methotrexate and ifosfamide in the perioperative treatment of osteosarcoma patients were safe and tolerable. Postoperative good response rate was similar to previously reported results. Survival follow-up is still ongoing to analyze the effect of perioperative immunotherapy combined with chemotherapy on long-term outcomes of patients with osteosarcoma. Clinical trial information: NCT04294511 .

Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer.

9056 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in a variety of tumor types, including lung cancer. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor that demonstrated rapid, deep, and durable responses in patients (pts) with TRK fusion lung cancer (Drilon et al. ASCO 2022) and is considered a preferred first-line therapy option for these pts (Owen et al. J Clin Oncol 2022). We report updated data from a larger cohort with longer follow-up. Methods: Pts with TRK fusion lung cancer enrolled in 2 larotrectinib clinical trials (NCT02576431 and NCT02122913) were included in this analysis. Larotrectinib was administered at 100 mg twice daily, and response was assessed by independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2022, 30 pts with a median age of 55.5 years (range 25–81) with TRK fusion lung cancer enrolled, including 12 pts with CNS metastases at baseline. The gene fusions involved NTRK1 (n = 24; 80%) or NTRK3 (n = 6; 20%). Pts received a median of 2 prior lines of systemic therapies, with 20 pts (67%) receiving ≥2. Among 27 pts eligible for IRC assessment, the objective response rate (ORR) was 74% (95% CI 54–89): 3 complete responses, 17 partial responses (PR), 4 stable disease (SD), 2 progressive disease (PD), and 1 not evaluable. Among the 12 pts with baseline CNS metastases, the ORR was 67% (95% CI 35–90): 8 PR, 2 SD, and 2 PD. The median time to response for all responders was 1.8 months. Median duration of response (DoR) was 33.9 months (95% CI 9.5–not estimable [NE]); median follow-up was 22.9 months. Median progression-free survival (PFS) was 33.0 months (95% CI 11.3–NE); median follow-up was 24.7 months. Median overall survival (OS) was 39.3 months (95% CI 17.2–NE); median follow-up was 23.1 months. For the 12 pts with CNS metastases, the medians for DoR, PFS, and OS were 9.5, 9.9, and 19.4 months, with median follow-ups of 17.4, 19.3, and 22.2 months, respectively. Duration of treatment for all pts evaluable per IRC ranged from 0.3+ to 75.2+ months. At data cut-off, 10 pts had progressed, with 6 continuing treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade 3–4 TRAEs were reported in 5 pts (2 each increased aspartate aminotransferase, increased weight; 1 each increased alanine aminotransferase, myalgia, hypersensitivity). There were no treatment discontinuations due to TRAEs. Conclusions: In this larger dataset with longer follow-up, larotrectinib continued to demonstrate rapid and durable responses, extended survival, and favorable long-term safety in pts with advanced TRK fusion lung cancer, including those with CNS metastases. These results support the wider adoption of next-generation sequencing testing for NTRK1–3 gene fusions in pts with lung cancer. Clinical trial information: NCT02576431 , NCT02122913 .

Pegylated liposomal doxorubicin combined with ifosfamide for advanced soft tissue sarcomas: A phase I dose-escalation study.

e23525 Background: Doxorubicin combined with ifosfamide (IFO) is one of the preferred treatment options for non-specific soft tissue sarcomas (STS), but is limited by cumulative cardiotoxicity and severe myelosuppression. Pegylated liposomal doxorubicin (PLD) provides an effective alternative to conventional anthracyclines with reduced toxicity. However, there is no standard dose recommendation for PLD combined with IFO for STS. The present study aimed to investigate the maximum tolerated dose (MTD) of PLD combined with IFO in advanced STS patients. Methods: This was a phase I, open-label, single-center, dose-escalation study. Patients with locally advanced or metastatic STS were enrolled, except for gastrointestinal stromal tumors, Ewing's sarcomas, embryonal rhabdomyosarcomas, and alveolar rhabdomyosarcomas. We used a standard 3 + 3 dose-escalation design with progressively increasing PLD and IFO (3 g/m2 per day for 3 days, q3w) for one cycle, with a dose escalation ranged from 30 to 70 mg/m2 (5mg/m2 increment per step). The primary endpoint was determination of the MTD, and the secondary endpoint was the incidence/severity of adverse events (AEs). Results: From January 2020 to September 2022, 23 patients were enrolled in this study, including 3 patients at doses 30-45 mg/m2, 6 patients at dose 50 mg/m2, and 5 patients at 55 mg/m2. The median age was 49 years (ranges from 30 to 68 years), the male/female ratio was 12/11, and 22 (95.65%) patients had stage IV disease (AJCC staging system). Initially, no DLT was observed at doses of 30-50 mg/m2, with 3 patients in each dose phase. Two patients developed DLTs at the 55 mg/m2 dose, resulting in the 50 mg/m2 dose extending to a total of 6 patients who completed treatment without DLT. The DLTs at dose 55 mg/m2 of the first patient were grade 4 neutropenia lasting ≥ 5 days and grade 3 thrombocytopenia with hemorrhage tendency; the second patient had grade 4 neutropenia lasting ≥ 5 days, grade 4 thrombocytopenia relapsed after platelet transfusion, and grade 3 increased alanine aminotransferase. Therefore, the MTD of PLD was 50 mg/m2. The most common (≥ 10%) grade 3-4 AEs in all patients were lymphopenia (56.52%), neutropenia (82.61%), leukopenia (86.96%), and thrombocytopenia (13.04%). Conclusions: For patients with locally advanced or metastatic STS, single cycle PLD combined with IFO had a tolerable AE profile, with an MTD of 50 mg/m2 for PLD. Further researches are needed to confirm the multi-cycle recommendation. Clinical trial information: ChiCTR1900028270 .

Safety and efficacy of HB0025, an anti-PD-1/VEGF bispecific antibody fusion protein, in patients with advanced solid tumors: Preliminary results from an FIH trial.

2589 Background: HB0025 is a recombinant humanized anti-PD-L1 monoclonal antibody-VEGFR1 fusion Protein. Nonclinical data both in vitro and vivo have shown high-affinity binding to both targets as well as the inhibition of tumor growth in animal models. Here, we present preliminary safety and efficacy data from a dose escalation phase I study of HB0025. Methods: Eligible patients(pts) were ≥18 years old (ECOG PS 0–1) who had advanced solid tumors (NSCLC, gynecological tumors, digestive system tumors, etc.) and failed standard treatment. This phase 1 dose escalation includes accelerated titration (0.01, 0.03, 0.1 and 0.3mg/kg) and conventional 3+3 dose escalation (1.0, 3.0, 6.0, 10, 12, 20, and 30.0 mg/kg). HB0025 is administered intravenously every 14 days (Q2W). Objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and antitumor activity. Adverse events (AEs) were reported with CTCAE v5.0 and DLTs were evaluated within a 28-day window. Results: As of Aug 30th 2022, 30 pts including 8 male and 22 female from Caucasian and Mongoloid have received HB0025 at doses of 0.01 mg/kg (n=1), 0.03 mg/kg (n=2), 0.1 mg/kg (n=1), 0.3 mg/kg (n=1),1.0 mg/kg (n=3), 3.0 mg/kg (n=7), 6.0mg/kg (n=7), 10.0 mg/kg (n=5), and 12.0mg/kg (n=3) Q2W. Overall, the median age was 55 years and the median lines of previous treatment was four. Of the 22 evaluable pts dosed at ≥ 3 mg/kg Q2W, the ORR was 9.1% (2/22) and the disease control rate (DCR) was 50% [11/22]. Among the 2 responders, a CR (colorectal ca) pt whose prior therapy was no immune checkpoint inhibitor (ICI) or bevacizumab have continued more than 36 weeks; and a PR (NSCLC) pt with duration more than 18 weeks whose tumor was 60.2% regression and prior ICI failure. Till the date of submission, the therapy was continuing for the CR and PR pts. Treatment-related adverse events (TRAEs) occurred in 83.3% of pts. The grade 3 TRAEs occurred in 20% [6/30] and treatment-related SAEs occurred in 13.3% [4/30]. One DLT occurred in the 12.0mg/kg cohort. No death occurred related to HB0025. TRAEs leading to treatment discontinuation occurred in 13.3% of pts [4/30]. The most frequent TRAEs were hypertriglyceridemia (23.3%), hypercholesterolemia (23.3%), anemia (16.7%), alanine aminotransferase increase (16.7%), and proteinuria (13.3%). Conclusions: HB0025 shows manageable safety and promising anti-tumor activity in pts with various solid tumors. To better characterize the risk-benefit profile, HB0025 is currently enrolled at 20.0 mg/kg Q2W and is being explored at doses 10 mg/kg in expansion cohorts. The future data, including PK, PD and ADA will be presented. Clinical trial information: NCT04678908 .

Tolerability and toxicity profiles of antibody-drug conjugates for the treatment of malignant neoplasms: A meta-analysis of randomized clinical trials.

e15011 Background: Antibody-drug conjugates (ADCs) are attractive targeted agents in anticancer treatment due to their unique mechanism of action and reduced toxicity compared to other anti-cancer drugs. Yet little is still known about the adverse events profiles associated with ADCs. Methods: A systematic review was performed including randomized controlled trials (RCTs) of anticancer treatment that evaluated the efficacy of ADCs. PubMed and EMBASE were systematically searched for studies from January 1990 to December 2022. RCTs that were registered in ClinicalTrials.gov and had final reports of comprehensive adverse events were also included. We included studies for patients with both solid and hematologic tumors. The odds ratios (ORs) of treatment-related symptoms, and hematologic, hepatic, ocular, cardiovascular, renal, and respiratory toxicities for patients treated with ADCs and those without ADCs were examined. A random effects model was developed to estimate the pooled ORs of each adverse event associated with ADC use. Subgroup analyses were also performed based on the cancer type (solid tumors versus hematologic malignancy) and ADC regimen (ADC versus ADC plus chemotherapy). Results: 20 studies involving 10,075 patients (5,745 patients with ADC and 4,330 patients without ADC) were included. Among the included trials, 14 (70.0%) were trials for solid tumors and 6 (30.0%) were trials for hematological tumors. Among the included trials, ADC monotherapy was used in 15 (75.0%) experimental arms, and combination therapy of ADC with any other chemotherapy was used in 7 (35.0%). ADCs were associated with a higher risk for all-grade fatigue (OR 1.25, 95% CI 1.08-1.45), anorexia (OR 1.36, 1.09-1.69), nausea (OR 1.46, 1.09-1.97) and sensory neuropathy (OR 2.18, 1.27-3.76). Patients treated with ADCs had a significantly lower risk of all-grade febrile neutropenia (OR 0.46, 0.22-0.96), leukopenia (OR 0.47, 0.29-0.77), and neutropenia (OR 0.56, 0.31-1.01). Whereas, they had a higher risk of all-grade increased alanine aminotransferase (OR 2.51, 1.84-3.40), increased aspartate aminotransferase (OR 2.83, 2.04-3.93), cataract (OR 4.69, 1.86-11.81), blurry vision (OR 3.12, 1.02-9.55), pericardial effusion (OR 4.27, 2.71-6.72), and epistaxis (OR 2.45, 1.50-4.01). In the subgroup analysis, a similar toxicity profile was observed when comparing the solid tumors versus hematologic malignancy groups and the ADC versus ADC plus chemotherapy groups, except for hematologic adverse events, which showed an increased risk in patients with solid tumors and those treated with both chemotherapy and ADCs. Conclusions: This comprehensive profile of adverse events associated with ADC-based treatment shows increased treatment-related symptoms, hepatic, ocular, and cardiovascular toxicities although no increase of high-grade are seen.

A phase 1 dose-escalation study of RiMO-301 with palliative radiation in advanced tumors.

2527 Background: Nanoscale metal−organic frameworks (MOFs) are a new class of organic−inorganic hybrid nanomaterials constructed from metal centers and organic ligands. Preclinical studies have shown that nanoscale MOFs can enhance the antitumor effects of ionizing radiation via a unique radiotherapy-radiodynamic therapy mode of action, and MOFs plus radiation can enhance the immunotherapeutic effects of immune checkpoint inhibitors. RiMO-301 is a hafnium-based MOF which enhances radiotherapy and checkpoint blockade immunotherapy without showing systemic toxicity in preclinical models. RiMO-301 is the first MOF to enter clinical trials on human patients. Methods: This is a multicenter, open-label, first-in-human dose-escalation phase I trial of RiMO-301 [NCT03444714]. The primary objective is to determine the maximum tolerated dose (MTD) of locally injected RiMO-301 with or without the PD-1 inhibitor pembrolizumab in patients treated with concurrent palliative doses of radiation (20 Gy in 5 fractions or 30 Gy in 10 fractions) using a 3+3 design. The MTD is defined as the dose associated with dose-limiting toxicity (DLT) in less than 33% of patients. The secondary objective is to evaluate antitumor response (objective response rate, ORR) using RECIST and itRECIST criteria. Results: A total of 25 patients were enrolled and treated with escalating doses of RiMO-301 (relative to tumor volumes). No protocol defined DLT was reported. The observed possibly treatment related adverse events included mild dermatitis radiation, mild dysgeusia, diarrhea, mild hypotension (30 days post treatment) and mild dizziness (30 days post treatment). One patient each experienced a Grade 2 alanine aminotransferase increase 45 days post treatment, a Grade 2 dry mouth, and a Grade 3 pain at the injection site. Nineteen patients were evaluable, with 13 and 6 patients, respectively, for RiMO-301 without and with pembrolizumab treatments. By itRECIST criteria, RiMO-301 without pembrolizumab demonstrated 38.5% (5/13) ORR (1 complete response and 4 partial responses) with 2 additional patients experiencing 20-30% tumor size reduction. RiMO-301 with pembrolizumab exhibited 66.7% (4/6) ORR with the 2 remaining patients showing 15-20% tumor size reduction. Preliminary pharmacokinetic analysis indicated that the hafnium concentrations in the systemic circulation were either below or barely above the level of detection. Conclusions: RiMO-301 with or without pembrolizumab was well tolerated and demonstrated promising signs of efficacy in patients with advanced tumors when treated with concurrent palliative radiotherapy. The results support the use of RiMO-301 as a potential radio-enhancer and will prompt further phase 2 studies in the development of RiMO-301 for patients undergoing radiotherapy. Clinical trial information: NCT03444714 .

Wildfire-related smoke inhalation worsens cardiovascular risk in sleep disrupted rats.

As a lifestyle factor, poor sleep status is associated with increased cardiovascular morbidity and mortality and may be influenced by environmental stressors, including air pollution. To determine whether exposure to air pollution modified cardiovascular effects of sleep disruption, we evaluated the effects of single or repeated (twice/wk for 4 wks) inhalation exposure to eucalyptus wood smoke (ES; 964 μg/m3 for 1 h), a key wildland fire air pollution source, on mild sleep loss in the form of gentle handling in rats. Blood pressure (BP) radiotelemetry and echocardiography were evaluated along with assessments of lung and systemic inflammation, cardiac and hypothalamic gene expression, and heart rate variability (HRV), a measure of cardiac autonomic tone. GH alone disrupted sleep, as evidenced by active period-like locomotor activity, and increases in BP, heart rate (HR), and hypothalamic expression of the circadian gene Per2. A single bout of sleep disruption and ES, but neither alone, increased HR and BP as rats transitioned into their active period, a period aligned with a critical early morning window for stroke risk in humans. These responses were immediately preceded by reduced HRV, indicating increased cardiac sympathetic tone. In addition, only sleep disrupted rats exposed to ES had increased HR and BP during the final sleep disruption period. These rats also had increased cardiac output and cardiac expression of genes related to adrenergic function, and regulation of vasoconstriction and systemic blood pressure one day after final ES exposure. There was little evidence of lung or systemic inflammation, except for increases in serum LDL cholesterol and alanine aminotransferase. These results suggest that inhaled air pollution increases sleep perturbation-related cardiovascular risk, potentially in part by increased sympathetic activity.