Investigational New Drugs最新文献

{"title":"First-in-human, phase 1 dose escalation study of SL-279252, a hexameric PD1-Fc-OX40L fusion protein, in patients with advanced solid tumors and lymphoma.","authors":"Melissa Johnson, David Hong, Irene Braña, Patrick Schöffski, Vladimir Galvao, Fatima Rangwala, Bo Ma, Robert Hernandez, Asha Kamat, Kazunobu Kato, Taylor H Schreiber, Lini Pandite, Lillian L Siu","doi":"10.1007/s10637-025-01518-7","DOIUrl":"https://doi.org/10.1007/s10637-025-01518-7","url":null,"abstract":"<p><p>SL-279252 is a bifunctional hexameric fusion protein adjoining the extracellular domains of PD-1 and OX40L via an inert IgG4 derived Fc domain. A Phase 1 dose escalation study was conducted in patients (pts) with advanced solid tumors or lymphomas. SL-279252 was administered intravenously across 12 dose levels (range: 0.0001-24 mg/kg). Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic (PD) parameters, and anti-tumor activity. Forty-nine pts (48 with solid tumor and 1 with lymphoma) were enrolled (median age 64 years; 53% male; median [range] of 3 [0-5] prior systemic therapies; 61% had been previously treated with PD-1/L1 inhibitors). Most common treatment-related adverse events (AEs) were infusion-related reaction (16%), maculopapular rash (10%), fatigue (6%), and neutropenia (6%). Treatment-related Grade (G) 3 AE was neutropenia (4%). There were no G4 or G5 AEs or DLTs. SL-279252 Cmax and area under the curve (AUC) increased proportionally with dose. T½ was ~ 20 h. Baseline anti-drug antibodies (ADA) were observed in 11/42 pts who had received a PD-1 inhibitor within 250 days. 7/31 pts had a persistent SL-279252 induced ADA response. PD effects consistent with OX40 engagement included dose dependent egress of CD4 + OX40 + cells and increases in Ki67 + CD4 and CD8 central and effector memory cells in the blood. Best response by iRECIST [1] in 46 response evaluable subjects was 1 iPR and 15 iSD. SL-279252 was well tolerated. PD effects consistent with OX40 activation were observed, however, efficacy was limited which may have been due to the disease characteristics, prior treatment with PD-1/L1 inhibitors, neutralization of the PD-1 domain of SL-279252 by circulating PD-1 inhibitors, limited SL-279252 penetration into tumors or other variables. Trial register number NCT03894618. Trial registration date 28-March-2019.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From development to clinical success: the journey of established and next-generation BTK inhibitors.","authors":"Shivani Gupta, Arpit Sharma, Alok Shukla, Abha Mishra, Amit Singh","doi":"10.1007/s10637-025-01513-y","DOIUrl":"https://doi.org/10.1007/s10637-025-01513-y","url":null,"abstract":"<p><p>Over the past decade, Bruton's tyrosine kinase (BTK) has emerged as a pivotal therapeutic target for B-cell malignancies and autoimmune diseases, given its essential role in B-cell development and function. Dysregulation of BTK signalling is implicated in a range of hematologic cancers, including Waldenström's macroglobulinaemia (WM), mantle cell lymphoma (MCL), and chronic lymphocytic leukaemia (CLL). The development of BTK inhibitors (BTKIs), starting with ibrutinib, has revolutionized the treatment of these malignancies by inhibiting B-cell receptor (BCR) signalling and inducing apoptosis in malignant B-cells. Despite the impressive clinical efficacy of ibrutinib, challenges such as resistance mutations and off-target effects remain. To address these issues, next-generation BTKIs, including acalabrutinib, orelabrutinib, zanubrutinib, and pirtobrutinib, have been developed, offering improved specificity and reduced toxicity profiles. This review highlights the therapeutic potential of BTK-targeted therapies in treating B-cell malignancies, discusses recent advancements with FDA-approved BTKIs, and explores the latest clinical outcomes from ongoing trials of novel inhibitors.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retrospective analysis of clinical features of nivolumab-induced immune-related pancreatitis.","authors":"Yong Pan, Wei Li, Zhaoquan Wu, Wei Sun, Binsheng He, Chunjiang Wang","doi":"10.1007/s10637-025-01517-8","DOIUrl":"https://doi.org/10.1007/s10637-025-01517-8","url":null,"abstract":"<p><p>To study the clinical features of nivolumab-induced immune-related pancreatitis and to provide evidence for its recognition and treatment. Cases of nivolumab-induced pancreatitis were collected by searching Chinese and English databases until November 30, 2024. Forty-three patients were included, with a median age of 61 years (range 23, 79). The median time to onset of pancreatitis was 120 days (range 1, 990) after initial administration. The main symptoms of the patients were abdominal pain (55.8%), nausea (14.0%), vomiting (11.6%), fever (9.3%), anorexia (9.3%), and asymptomatic (7.0%). Laboratory tests showed elevated lipase and amylase levels, with median values of 391.5 IU/L (range 136, 4050) and 1588 IU/L (range 248, 8788), respectively. Pancreatic biopsy showed inflammatory cell infiltration (18.6%), fibrosis (7.0%), and acinar damage and dropout (4.7%). The main imaging findings were focal or diffuse enlargement of the pancreas and fat stranding. After discontinuation of nivolumab and receiving steroid and immunosuppressive therapy (88.4%), patients' symptoms improved at a median time of 42 days (range 7, 192), and 11.6% of patients died. Immune-related pancreatitis should be alert during nivolumab administration. The lack of specificity of clinical symptoms and laboratory tests confuses the diagnosis of pancreatitis. The diagnosis of immune-associated pancreatitis should be treated promptly.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel anti-HER2/EGFR bispecific antibody-drug conjugate demonstrates promising antitumor efficacy and overcomes resistance to HER2- or EGFR-targeted ADCs.","authors":"Huoying Huang, Yuxin Zhou, Chengzhang Shang, Yifu Zhang, Yuelei Shen","doi":"10.1007/s10637-025-01507-w","DOIUrl":"https://doi.org/10.1007/s10637-025-01507-w","url":null,"abstract":"<p><p>HER2 and EGFR are frequently co-expressed in various tumors. While antibody-drug conjugates (ADCs) targeting HER2, such as T-DM1 and T-Dxd, have shown remarkable antitumor effects in clinical responses, their effectiveness is constrained by drug resistance. EGFR amplification or high expression is one of the factors that lead to resistance against HER2-targeted ADCs. Likewise, the amplification of HER2 may lead to the development of resistance to EGFR-targeted therapies. To overcome these challenges, we, therefore, developed a bispecific antibody (B2C4) that targets HER2 and EGFR. B2C4 exhibited strong binding affinity and internalization activity in tumor cells with high expression of HER2 and EGFR, as well as in those with high expression of either target. B2C4 was then conjugated with vc-MMAE to create a bispecific ADC (B2C4-MMAE) with an average DAR of 4.05. By effectively engaging both arms of the bispecific ADC, B2C4-MMAE demonstrated significant antitumor activity in tumor cells and animal models that were unresponsive HER2- or EGFR-targeted ADCs. B2C4-MMAE could serve as an alternative therapeutic option for tumors that are resistant to single-target treatments. Additionally, B2C4-MMAE exhibited potential in treating tumors resistant to T-Dxd, underscoring its promise as a treatment for challenging cases.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase I dose-escalation and expansion study of RMX1002, a selective E-type prostanoid receptor 4 antagonist, as monotherapy and in combination with anti-PD-1 antibody in advanced solid tumors.","authors":"Dan Liu, Jifang Gong, Jian Zhang, Yongqian Shu, Hao Wu, Tianshu Liu, Yanhua Xu, Lijia Zhang, Min Li, Xichun Hu, Lin Shen","doi":"10.1007/s10637-025-01512-z","DOIUrl":"https://doi.org/10.1007/s10637-025-01512-z","url":null,"abstract":"<p><p>RMX1002 (grapiprant) is a selective E-type prostanoid receptor 4 (EP4) antagonist and a promising candidate for cancer therapy, potentially enhancing anti-tumor immune responses. This study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of RMX1002 as monotherapy and in combination with anti-PD-1 antibody toripalimab for advanced solid tumors. This multicenter, phase I trial enrolled patients with histologically or cytologically confirmed advanced solid tumors. This study included three phases: Ia (dose-escalation of RMX1002 monotherapy from 200 to 650 mg BID), Ib (dose-escalation from 500 to 650 mg BID in combination with toripalimab), and Ic (dose-expansion of 500 mg BID with toripalimab). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. A total of 45 patients were enrolled (17 in phase Ia, 12 in phase Ib, and 16 in phase Ic). No dose-limiting toxicity was reported, and the MTD was not reached. Overall, 21 patients experienced RMX1002-related adverse events with CTCAE grade ≥ 3. Pharmacokinetics revealed rapid absorption of RMX1002 with the maximum concentration (C_max) reached within 2 to 5 h, and dose-dependent increases in C_max and area under the concentration-time curve. The increase in urinary metabolite of PGE2 suggested the inhibition of EP4 signaling pathway. The best response was stable disease, reported in 64.7%, 28.6%, and 18.8% of patients in phase Ia, Ib, and Ic, respectively. RMX1002 was well tolerated and showed a best response of stable disease. RMX1002 500 mg BID with toripalimab 240 mg every 3 weeks is the recommended dose for future trials.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: results of a single-center, multi-arm phase Ib study.","authors":"Kyaw Z Thein, Daniel D Karp, Apostolia Tsimberidou, Jing Gong, Selma Sulovic, Jatin Shah, Denái R Milton, David S Hong, Filip Janku, Lacey McQuinn, Bettzy A Stephen, Rivka Colen, Brett W Carter, Timothy A Yap, Sarina A Piha-Paul, Siqing Fu, Funda Meric-Bernstam, Aung Naing","doi":"10.1007/s10637-024-01493-5","DOIUrl":"https://doi.org/10.1007/s10637-024-01493-5","url":null,"abstract":"","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenging and new opportunities for prodrug technology.","authors":"Helin Li, Xuelian Shen, Yu Chu, Panhong Yuan, Qi Shuai","doi":"10.1007/s10637-025-01515-w","DOIUrl":"https://doi.org/10.1007/s10637-025-01515-w","url":null,"abstract":"<p><p>Research on prodrug technology has opened new avenues for site-directed chemotherapy rather than systemic chemotherapy. This distinctive strategy allows drug delivery to be activated by light-, irradiation-, or ultrasound (US)-tunable chemistries, which have been termed photopharmacology, radiopharmacology, and sonopharmacology, respectively. Prodrugs have emerged as a main strategy for improving pharmacokinetics, reducing side effects, and thus enhancing the therapeutic efficacy of drugs. This review summarizes stimuli-responsive drug release systems and the latest progress in exogenous stimuli-responsive prodrug activation, e.g., light, irradiation, and US, with a focus on the activation of small molecule prodrugs, antibody‒drug conjugates, and prodrug nanosystems. In addition, challenges encountered by Pt drugs and Pt(IV) prodrug nanotherapeutics are summarized and discussed. Moreover, this review presents the current state of precise treatment and discusses the opportunities and challenges for the clinical translation of these strategies.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardioprotective effects of PARP inhibitors for platinum-agent induced cardiotoxicity.","authors":"Jae Hyun Kim, Ja-Young Han, Jae-Hee Kwon, Myeong Gyu Kim","doi":"10.1007/s10637-025-01509-8","DOIUrl":"https://doi.org/10.1007/s10637-025-01509-8","url":null,"abstract":"<p><p>Poly(ADP-ribose) polymerase (PARP) inhibitors may have cardioprotective properties. This study aimed to evaluate the potential cardioprotective effects of PARP inhibitors in patients with epithelial ovarian cancer treated with platinum-based chemotherapeutic agents. A retrospective cohort study was conducted using the Health Insurance Review & Assessment Service claims database from January 2007 to July 2022. Eligible patients were those diagnosed with ovarian, primary peritoneal, or fallopian tube cancer who received platinum-based chemotherapy after 2017. Propensity score matching was employed to adjust for potential confounders, and logistic regression and Cox proportional hazards regression analyses were utilized to estimate the odds ratios, hazard ratios, and 95% confidence intervals (CIs) for the occurrence of cardiac adverse events, including myocardial infarction, cardiomyopathy, and heart failure. A total of 7,253 eligible patients were included in the study, of which 233 (3.2%) used PARP inhibitors. After propensity score matching, no significant cardioprotective effect was observed in the PARP inhibitor-exposed group compared to the non-exposed group (adjusted odds ratio, 0.753; 95% CI 0.275-2.059; adjusted hazard ratio, 0.601; 95% CI 0.228-1.584). Although no statistically significant cardioprotective effect of PARP inhibitors was found in this study, there was a directional trend suggesting that patients with gynecologic malignancies treated with platinum-based chemotherapy could potentially benefit from PARP inhibitors. Further research with larger sample sizes and longer follow-up periods is warranted to elucidate the role of PARP inhibitors in mitigating cardiac adverse events in this patient population.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress of KRAS G12C inhibitors in the treatment of refractory colorectal cancer and strategies for drug resistance response.","authors":"Peiyuan Yang, Yongchao Li","doi":"10.1007/s10637-025-01514-x","DOIUrl":"https://doi.org/10.1007/s10637-025-01514-x","url":null,"abstract":"<p><p>Colorectal cancer is the third most prevalent cancer in the world. Early screening and detection of tumours, active surgical radical treatment, postoperative adjuvant chemotherapy, targeted therapy, and immunotherapy are performed based on pathological staging and immunohistochemistry. Even with these measures, the 5-year survival rate of colorectal cancer is only 65%, and a considerable number of patients still experience tumour recurrence or even metastasis. The KRAS G12C mutation accounts for 3 to 4% of refractory colorectal cancer (advanced or metastatic colorectal cancer), and it was once believed that KRAS did not have a drug target until the emergence of KRAS G12C inhibitors provided targeted treatment for KRAS-mutated colorectal cancer. However, KRAS G12C inhibitors only produce moderate efficacy, and resistance occurs after a short remission. The mechanism of drug resistance in tumour cells is complex and diverse, and existing research has limited understanding of it. This review aims to elucidate the clinical trial progress of KRAS G12C inhibitors in refractory colorectal cancer, the research progress of drug resistance mechanisms, and the combined treatment strategies for drug resistance.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC6 inhibition through WT161 synergizes with temozolomide, induces apoptosis, reduces cell motility, and decreases β-catenin levels in glioblastoma cells.","authors":"Leilane Sales Oliveira, João Marcos Oliveira-Silva, Hebreia Oliveira Almeida-Souza, Mario Machado Martins, Carolina Berraut Chiminazo, Rafael Fonseca, Carlos Vinicius Expedito de Souza, Alexandre Ferro Aissa, Luciana Machado Bastos, Marisa Ionta, Graziela Domingues de Almeida Lima, Angel Mauricio Castro-Gamero","doi":"10.1007/s10637-025-01508-9","DOIUrl":"https://doi.org/10.1007/s10637-025-01508-9","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) accounts for 70% of all primary malignancies of the central nervous system. Current treatment strategies involve surgery followed by chemotherapy with temozolomide (TMZ); however, the median survival after treatment is approximately 15 months. Many GBM cases develop resistance to TMZ, resulting in a poor prognosis for patients, which underscores the urgent need for novel therapeutic approaches. One promising avenue is the inhibition of histone deacetylase 6 (HDAC6), an enzyme that deacetylates α-tubulin and is increasingly recognized as a potential pharmacological target in cancer. In GBM specifically, HDAC6 overexpression has been linked to poor prognosis and chemoresistance. In this study, we demonstrate that HDAC6 protein levels are elevated in GBM and evaluate the effects of the novel selective HDAC6 inhibitor, WT161, on U251, U87, and T98G cells to assess its potential to revert the malignant phenotype. Our results show a significant increase in acetylated α-tubulin levels, suppression of cell growth, cell cycle arrest at the G2/M phase, and decreased clonogenicity of 2D-cultured GBM cells. Additionally, WT161 acted synergistically with TMZ, induced apoptosis and enhanced TMZ-induced apoptosis. Notably, HDAC6 inhibition resulted in reduced cell migration and invasion, associated with decreased β-catenin levels. When cultured in 3D conditions, WT161-treated T98G spheroids were sensitized to TMZ and exhibited reduced migration. Finally, HDAC6 inhibition altered the metabolome, particularly affecting metabolites associated with lipid peroxidation. In conclusion, our data reveal, for the first time, the efficacy of the selective HDAC6 inhibitor WT161 in a preclinical GBM setting.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}