Investigational New Drugs最新文献

The therapeutic effects of many pharmacotherapies have been explored, but disadvantages such as low drug specificity, drug resistance and side effects makes their effective delivery to target sites a great challenge. Consequently, a distinctive prodrug-based technology have emerged as an effective treatments because of their distinctive advantages, such as high drug loading capacity, precise targeting, reduced side effects and spatial and temporal controllability. In particular, the use of gamma/X-ray-mediated strategies in radiotherapy is a new strategy that could enable the precise drug release from implanted devices. This review presents readers with the current state of prodrug therapy and reports the design protocols of rational and effective prodrugs for clinical use.

Background: Relugolix has been used to treat advanced prostate cancer. This study assessed adverse events (AEs) associated with relugolix from the US Food and Drug Administration Adverse Event Reporting System (FAERS).

Methods: Disproportionality analysis, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of relugolix-associated AEs.

Results: A total of 5,059,213 reports of AEs were collected from the FAERS database, of which 5,662 reports were identified with relugolix as the "primary suspect (PS)". A total of 70 significant disproportionality PTs conforming to the four algorithms were simultaneously retained. Unexpected new AEs, such as erectile dysfunction, gynaecomastia, testicular atrophy, male genital atrophy, libido decreased might also occur.

Conclusion: This study found potential new AEs signals and might provide important support for clinical monitoring and risk identification of relugolix.

This phase 1 first-in-human study evaluated the safety, tolerability, and pharmacokinetics of MK-1088, a novel, small-molecule dual inhibitor of adenosine A_2A and A_2B receptors. Healthy adult participants were enrolled in two panels (n = 8 each) and randomly assigned to receive MK-1088 (n = 6) or placebo (n = 2) orally in each of five treatment periods. Participants in panel A received single ascending doses of MK-1088 at 1, 10, 50, and 150 mg or placebo in a fasted or fed (50 mg only) state. Participants in panel B received MK-1088 at 3, 25, 100, and 224 mg or placebo in a fasted state. Primary objectives were to evaluate safety, tolerability, and plasma pharmacokinetics following a single dose of MK-1088. The secondary objective was to evaluate the effects of a high-fat meal on pharmacokinetics. All participants (n = 16) completed the study (median age: 33 years [range: 20-43]; all were male). Treatment-related adverse events (AEs) occurred in 1 of 6 (17%), 4 of 6 (67%), 4 of 6 (67%), and 2 of 6 (33%) participants after receiving MK-1088 at 3, 25, 100, and 224 mg, respectively. No serious AEs or deaths due to any cause occurred. MK-1088 was rapidly absorbed after a single dose; half-life was ~ 11 h in the 100-224 mg dose range. The target concentration at 12 h (> 0.3 µM) was exceeded at the 50-mg dose level. MK-1088 plasma pharmacokinetics increased dose proportionately. A high-fat meal did not significantly affect pharmacokinetics at the 50-mg dose. MK-1088 was well tolerated and demonstrated dose-proportional pharmacokinetic properties that were not affected by a high-fat meal.

Summary

Plocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies. This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors. Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62 years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5 mg/m²/Gem 1000 mg/m²) was the MTD. Accrual into DL7 (Plo 10.0 mg/m²/Gem 1000 mg/m²) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4 months occurred among 13 pts with ovarian cancer. The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5 mg/m²/Gem 1000 mg/m². No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.

Worldwide, pancreatic cancer (PC) is a major health problem and almost 0.5 million people were diagnosed with PC in 2020. In the United States, more than 64,000 adults will be diagnosed with PC in 2023. PC is highly resistant to currently available treatments and standard of care chemotherapies cause serious side effects. Most PC patients are resistant to clinical therapies. Combination therapy has showed superior efficacy over single-agent treatment. However, most therapy has failed to show a significant improvement in overall survival due to treatment-related toxicity. Developing efficacious clinically useful PC therapies remains a challenge. Herein, we show the efficacy of an innovative pathway modulator, p53-Activator Wnt Inhibitor-2 (PAWI-2) against tumors arising from human pancreatic cancer stem cells (i.e., hPCSCs, FGβ₃ cells). PAWI-2 is a potent inhibitor of tumor growth. In the present study, we showed PAWI-2 potently inhibited growth of tumors from hPCSCs in orthopic xenograft models of both male and female mice. PAWI-2 worked in a non-toxic manner to inhibit tumors. Compared to vehicle-treated animals, PAWI-2 modulated molecular regulators of tumors. Anti-cancer results showed PAWI-2 in vivo efficacy could be correlated to in vitro potency to inhibit FGβ₃ cells. PAWI-2 represents a safe, new approach to combat PC.

Radioresistance is an inevitable obstacle in the clinical treatment of inoperable patients with non-small cell lung cancer (NSCLC). Combining treatment with radiosensitizers may improve the efficacy of radiotherapy. Previously, the quinoline derivative 10E as new exporter of Nur77 has shown superior antitumor activity in hepatocellular carcinoma. Here, we aimed to investigate the radiosensitizing activity and acting mechanisms of 10E. In vitro, A549 and H460 cells were treated with control, ionizing radiation (IR), 10E, and 10E + IR. Cell viability, apoptosis, and cycle were examined using CCK-8 and flow cytometry assays. Protein expression and localization were examined using western blotting and immunofluorescence. Tumor xenograft models were established to evaluate the radiosensitizing effect of 10E in vivo. 10E significantly inhibited cell proliferation and increased their radiosensitivity while reducing level of p-BCRA1, p-DNA-PKs, and 53BP1 involved in the DNA damage repair pathway, indicating that its radiosensitizing activity is closely associated with repressing DNA damage repair. A549 cells showed low level of Nur77 and a low response to IR but 10E-treated A549 cells showed high level of Nur77 indicating that Nur77 is a core radiosensitivity factor and 10E restores the expression of Nur77. Nur77 and Ku80 extranuclear co-localization in the 10E-treated A549 cells suggested that 10E-modulated Nur77 nuclear exportation inhibits DNA damage repair pathways and increases IR-triggered apoptosis. The combination of 10E and IR significantly inhibits tumor growth in a tumor xenograft model. Our findings suggest that 10E acts as a radiosensitizer and that combining 10E with radiotherapy may be a potential strategy for NSCLC treatment.

The present study aimed to clarify the hypothesis that auger emitter ¹²⁵I particles in combination with PARP inhibitor Olaparib could inhibit pancreatic cancer progression by promoting antitumor immune response. Pancreatic cancer cell line (Panc02) and mice subcutaneously inoculated with Panc02 cells were employed for the in vitro and in vivo experiments, respectively, followed by ¹²⁵I and Olaparib administrations. The apoptosis and CRT exposure of Panc02 cells were detected using flow cytometry assay. QRT-PCR, immunofluorescence, immunohistochemical analysis, and western blot were employed to examine mRNA and protein expression. Experimental results showed that ¹²⁵I combined with Olaparib induced immunogenic cell death and affected antigen presentation in pancreatic cancer. ¹²⁵I in combination with Olaparib influenced T cells and dendritic cells by up-regulating CD4, CD8, CD69, Caspase3, CD86, granzyme B, CD80, and type I interferon (IFN)-γ and down-regulating Ki67 in vivo. The combination also activated the cyclic GMP-AMP synthase stimulator of IFN genes (Sting) pathway in Panc02 cells. Moreover, Sting knockdown alleviated the effect of the combination of ¹²⁵I and Olaparib on pancreatic cancer progression. In summary, ¹²⁵I in combination with Olaparib inhibited pancreatic cancer progression through promoting antitumor immune responses, which may provide a potential treatment for pancreatic cancer.

This phase 1b study aimed to evaluate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of HR070803, a novel nanoliposomal formulation of irinotecan, in combination with 5-fluorouracil and leucovorin in patients with pretreated advanced solid tumors. This study consisted of dose-escalation and expansion stages. Dose escalation was performed with a traditional 3 + 3 design; patients received intravenous infusion of HR070803 from 60 to 80 mg/m², followed by leucovorin (200 mg/m²) and 5-fluorouracil (2000 mg/m²) every 2 weeks. In the expansion stage, patients received treatments at selected tolerable dose. Fifteen patients received treatments at 60 mg/m² (n = 12) and 80 mg/m² (n = 3). DLTs occurred in 2 patients at 80 mg/m² (grade 2 neutropenia that resulted in a dose delay of ≥ 7 days, n = 1; grade 3 febrile neutropenia, n = 1). The MTD was determined to be 60 mg/m². The most frequent HR070803related adverse events included anorexia, leukopenia, neutropenia, nausea, fatigue, and diarrhea. SN-38, the active metabolite of irinotecan, exhibited lower maximum plasma concentrations and a prolonged terminal half-life when irinotecan was administered via nanoliposome compared to conventional injection. Overall, 4 patients achieved a partial response (confirmed, n = 2), and 9 had stable disease. The MTD of HR070803 was 60 mg/m² when infused with 5-fluorouracil and leucovorin. Nanoliposomal encapsulation modified the pharmacokinetics of irinotecan and SN-38. HR070803 with 5-fluorouracil and leucovorin demonstrated a manageable safety profile and promising antitumor efficacy in advanced solid tumors. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05086848. Retrospectively registered on Oct. 12, 2021.

Acute pancreatitis (AP) is a rare adverse event of pembrolizumab with unclear clinical features. This study investigated the clinical features of pembrolizumab-induced AP to provide a reference for prevention and treatment. Case reports, case series and clinical studies of pembrolizumab-induced AP were collected by searching Chinese and English databases up to January 31, 2024. Thirty-one patients were included, with a median age of 59 years (range 39, 82). The median time from administration to onset of AP was 5.05 months (range 0.5, 16) and the median cycle was 7 cycles (range 1, 35). Twenty-two (71.0%) patients had elevated pancreatic amylase with a median value of 860 IU/L (range 105-12562), and 16 (51.6%) patients had elevated lipase with a median value of 282 IU/L (range 153-1034). Pancreatic biopsy showed neutrophil infiltration (9.7%) and lymphocyte infiltration (6.5%). Immunohistochemical staining showed CD8 dominated inflammatory infiltration (6.5%). The computed tomography showed diffuse enlargement (51.6%) and focal enlargement (51.6%) of the pancreas. Endoscopic ultrasound showed enlarged hypoechoic pancreas(16.1%). PET/CT showed increased FDG uptake (16.1%). The magnetic resonance cholangial pancreatography showed narrowing of main pancreatic duct (12.9%). AP symptoms and pancreatic enzymes improved after discontinuation of pembrolizumab and administration of steroids and infliximab. Clinicians should be aware that AP is a rare adverse reaction to pembrolizumab. Pembrolizumab induced AP can be initiated with steroids for control, and infliximab can be initiated with steroid-refractory AP.

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted.