Investigational New Drugs最新文献

{"title":"Anti-PD-L1 envafolimab combined with anti-VEGF suvemcitug in pretreated solid tumors and hepatocellular carcinoma: an open-label phase II study with safety run-in stage.","authors":"Lixia Ma, Yu Zhang, Yong Fang, Chunyi Hao, Qingxia Fan, Da Jiang, Liqin Lu, Fang Su, Chen Yang, Zhenru Liu, Ji Tian, Xiyang Sun, Shuguang Sun, Ying Cheng","doi":"10.1007/s10637-025-01506-x","DOIUrl":"https://doi.org/10.1007/s10637-025-01506-x","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC.</p><p><strong>Methods: </strong>This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR).</p><p><strong>Results: </strong>As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%.</p><p><strong>Conclusions: </strong>The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065559","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":"Targeting MYC for the treatment of breast cancer: use of the novel MYC-GSPT1 degrader, GT19630.","authors":"Minhong Tang, John Crown, Michael J Duffy","doi":"10.1007/s10637-024-01504-5","DOIUrl":"https://doi.org/10.1007/s10637-024-01504-5","url":null,"abstract":"<p><strong>Background: </strong>Since MYC is one of the most frequently altered driver genes involved in cancer formation, it is a potential target for new anti-cancer therapies. Historically, however, MYC has proved difficult to target due to the absence of a suitable crevice for binding potential low molecular weight drugs.</p><p><strong>Objective: </strong>The aim of this study was to evaluate a novel molecular glue, dubbed GT19630, which degrades both MYC and GSPT1, for the treatment of breast cancer.</p><p><strong>Methods: </strong>The antiproliferative potential of GT19630 was evaluated in 14 breast cancer cell lines representing the main molecular subtypes of breast cancer. In addition, we also investigated the effects of GT19630 on apoptosis, cell cycle progression, cell migration, and degradation of the negative immune checkpoint protein, B7-H3.</p><p><strong>Results: </strong>GT19630 inhibited cell proliferation, blocked cell cycle progression, promoted apoptosis, and decreased cell migration at low nanomolar concentrations in breast cancer cell lines. By contrast, previously described MYC inhibitors such as specific MYC-MAX antagonists affected these processes at micromolar concentrations. Consistent with the ability of MYC to promote immune evasion, we also found that GT19630 degraded the negative immune checkpoint inhibitor, B7-H3.</p><p><strong>Conclusions: </strong>We conclude that the novel molecular glue, GT19630, is a potent mediator of endpoints associated with cancer formation/progression. Its ability to degrade B7-H3 suggests that GT19630 may also promote host immunity against cancer. To progress GT19630 as a therapy for breast cancer, our finding should now be confirmed in an animal model system.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058797","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":"Synergistic antitumor effect of MK-1775 and CUDC-907 against prostate cancer.","authors":"Saisai Ma, Yichen Xu, Minmin Liu, Shuaida Wu, Ye Zhang, Hongyan Xia, Ji Lu, Yang Zhan","doi":"10.1007/s10637-024-01490-8","DOIUrl":"https://doi.org/10.1007/s10637-024-01490-8","url":null,"abstract":"<p><p>Due to the emergence of drug resistance, androgen receptor (AR)-targeted drugs still pose great challenges in the treatment of prostate cancer, and it is urgent to explore an innovative therapeutic strategy. MK-1775, a highly selective WEE1 inhibitor, is shown to have favorable therapeutic benefits in several solid tumor models. Recent evidence suggests that the combination of MK-1775 with DNA-damaging agents could lead to enhanced antitumor efficacy. Here, our results demonstrate that MK-1775 alone could indeed inhibit proliferation and induce apoptosis in prostate cancer. Moreover, the combination of MK-1775 and a dual PI3K and HDAC inhibitor, CUDC-907, can synergistically inhibit cell proliferation and dramatically induces apoptosis in prostate cancer cells. This effect is partially mediated by DNA damage, resulting from the downregulation of DNA damage response (DDR) proteins such as CDK, CHK, and RRM1/2. Notably, the combination of MK-1775 and CUDC-907 leads to significant antitumor effects in vivo. Our findings provide a strong basis for a promising combination strategy against prostate cancer.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046482","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":"Efficacy of ramucirumab combined with erlotinib or osimertinib in untreated EGFR-mutated NSCLC patients with asymptomatic brain metastases: insights from molecular biomarkers in the RELAY-brain trial.","authors":"Hiroyasu Kaneda, Haruko Daga, Asuka Okada, Yuki Nakatani, Yoko Tani, Takako Oka, Kenji Sawa, Kazuko Sakai, Kazuto Nishio, Tomoya Kawaguchi","doi":"10.1007/s10637-025-01505-y","DOIUrl":"https://doi.org/10.1007/s10637-025-01505-y","url":null,"abstract":"<p><strong>Background: </strong>The RELAY-Brain trial examined the clinical utility and survival impacts of ramucirumab (RAM) combined with epidermal growth factor receptor (EGFR)-TKI in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) with brain metastases. Although RAM combined with erlotinib (ERL) is known to have clinical benefits, the benefits in patients with baseline brain metastases remain unclear. This report examined the long-term follow-up data (Japan Registry of Clinical Trials: jRCTs2051190027) of the same patients, analyzing relevant biomarkers from tumor and plasma samples.</p><p><strong>Patients and methods: </strong>The six patients enrolled in the RELAY-Brain trial received RAM plus ERL or osimertinib (OSM). Our long-term follow-up observational study assessed patient survival, treatment status, and genetic biomarkers. Tumor and plasma samples were analyzed at baseline, during treatment, and at disease progression using next-generation sequencing and droplet digital PCR, to identify gene alterations and EGFR-TKI-resistant mutations.</p><p><strong>Results: </strong>After median follow-up of 44.2 months, the first site of disease progression in three of the patients was the brain metastases. In the RAM + ERL group, two patients with the T790M mutation subsequently received OSM. Progression-free survival (PFS) and overall survival ranged from 10.46 to 42.07 months and from 30.14 to 52.25 months, respectively. Gene alterations included TP53 mutations in three patients and ERBB2 and PIK3CA mutations in two. TP53 mutations were associated with shorter PFS.</p><p><strong>Conclusion: </strong>RAM with ERL or OSM achieved significant clinical benefits for patients with EGFR-mutated NSCLC with asymptomatic brain metastases. These positive outcomes and the identification of related biomarkers support the therapeutic potential of these combinations.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023473","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":"Linifanib alone and in combination with metronomic chemotherapy is active on cutaneous T-cell lymphoma cells by targeting the AKT/mTOR signaling pathway.","authors":"Marta Banchi, Maria Christina Cox, Arianna Bandini, Paola Orlandi, Costanza Tacchi, Fabio Stefanelli, Silvio Chericoni, Guido Bocci","doi":"10.1007/s10637-024-01501-8","DOIUrl":"https://doi.org/10.1007/s10637-024-01501-8","url":null,"abstract":"<p><p>Cutaneous T-cell lymphomas (CTCLs) are a rare and heterogeneous subset of skin-localized, non-Hodgkin lymphomas. Our aim was to evaluate the in vitro antitumor activity of the multi-kinase inhibitor linifanib, either alone or in combination with metronomic vinorelbine (mVNR) or etoposide (mETO), on CTCL cells. In vitro proliferation assay and Luminex analysis showed that long-term, daily exposure of linifanib significantly inhibited the proliferation of the human CTCL cell line HH, in a concentration-dependent manner (IC₅₀ = 48.4 ± 20.4 nM) and the phosphorylation of AKT/mTOR signaling pathway. The concomitant exposure of linifanib plus mVNR or mETO resulted in a strong synergism, with combination index values < 1. Linifanib significantly increased the VNR and ETO intracellular concentrations in HH cells, evaluated by UPLC-HRMS technology, and strongly reduced the ABCB1 and ABCG2 gene expression in HH. In conclusion, we reported a striking antitumor activity of daily, long-term linifanib and a clear synergistic effect when administered in combination with mCHEMO on CTCL cells, as a promising base for future clinical approaches in T-cell lymphomas.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005378","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":"Dual PTCH2 mutation [Ser391*, Leu104Pro]: unveiling a potential new genetic susceptibility factor for glioma development.","authors":"Xiang Li, Yingting Wu, Tiantian Han, Ran Ding, Rongrong Kong, Siqi Chen, Ningning Luo, Mingji Jin, Dongsheng Chen, Ping Zhang","doi":"10.1007/s10637-024-01491-7","DOIUrl":"https://doi.org/10.1007/s10637-024-01491-7","url":null,"abstract":"<p><p>Gliomas are a heterogeneous type of central nervous system tumor. The etiology of glioma formation remains elusive, with approximately 5% of gliomas being familial, underscoring the significance of understanding genetic susceptibility in glioma development. In this study, a dual germline PTCH2 mutation [Ser391*, Leu104Pro] was identified in a family with a history of glioma, and sequencing data from WES/SimcereDx Neuro-Onco 360 including 910 Chinese patients with glioma and 1666 patients with solid tumors were analyzed. A potential link between PTCH2 mutations and glioma development was observed in the Chinese population. Comprehensive analysis revealed that gliomas harboring dual PTCH2 mutations were segregated into two distinct clinical subtypes, indicating that the presence of PTCH2 is a novel genetic risk factor for glioma. These findings expand the genetic risk profile of glioma and offer promising avenues for the development of targeted diagnostic and therapeutic strategies. The results of this study emphasize the necessity for a comprehensive investigation into the genetic predisposition to gliomas, particularly in Asian populations, to achieve a better understanding of and management strategy for this complex disease.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970843","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":"Investigation of the association between therapeutic effectiveness of anamorelin and Glasgow prognostic score in patients with cancer cachexia: a competing risk analysis.","authors":"Kazuhiro Shimomura, Takatsugu Ogata, Akimitsu Maeda, Yukiya Narita, Hiroya Taniguchi, Kenta Murotani, Yutaka Fujiwara, Masahiro Tajika, Kazuo Hara, Kei Muro, Kosaku Uchida","doi":"10.1007/s10637-024-01503-6","DOIUrl":"https://doi.org/10.1007/s10637-024-01503-6","url":null,"abstract":"<p><p>Anamorelin, a highly selective ghrelin receptor agonist, enhances appetite and increases lean body mass in patients with cancer cachexia. However, the predictors of its therapeutic effectiveness are uncertain. This study aimed to investigate the association between the Glasgow prognostic score (GPS), used for classifying the severity of cancer cachexia, the therapeutic effectiveness of anamorelin, and the feasibility of early treatment based on cancer types. A retrospective analysis included patients with gastric, pancreatic, colorectal, and non-small-cell lung cancer treated with anamorelin between May 2021 and July 2022. The endpoints were the response rate for increased appetite within 3 weeks of treatment initiation and the time to treatment failure (TTF) due to therapeutic failure of anamorelin. Multivariate logistic regression model and Fine and Gray's model were used for analysis. Of the 137 patients in this analysis, 51% of patients had a GPS of 0 or 1, and 49% of those had a GPS of 2. Patients with a GPS of 2 showed a lower response for increased appetite than those with a GPS of 0 or 1 (adjusted odds ratio 0.29 [95% CI 0.12-0.72], P = 0.007). Additionally, TTF was shorter in patients with a GPS of 2 with a GPS of 0 or 1 (adjusted subdistribution hazard ratio 2.22 [95% CI 1.22-4.03], P = 0.009). Anamorelin could be more effective in improving appetite and prolonging the duration of treatment effect in patients with a GPS of 0 or 1 than those with a GPS of 2.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949008","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":"Stage-specific efficacy of osimertinib in treatment-naïve EGFR-mutant non-small cell lung cancer according to baseline genetic alterations in circulating tumor DNA.","authors":"Yoshihiko Taniguchi, Akihiro Tamiya, Mitsuo Osuga, Shun-Ichi Isa, Keiichi Nakamura, Yasuyuki Mizumori, Tsutomu Shinohara, Hidetoshi Yanai, Katsumi Nakatomi, Masahide Oki, Masahide Mori, Tomohito Kuwako, Koji Yamazaki, Masahiro Shimada, Masahiko Ando, Yasuhiro Koh","doi":"10.1007/s10637-024-01500-9","DOIUrl":"https://doi.org/10.1007/s10637-024-01500-9","url":null,"abstract":"<p><p>The impact of clinical stage on the effectiveness of osimertinib for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) remains unexamined. We investigated osimertinib therapeutic efficacy variation between stage IVA or lower and stage IVB EGFR mutation-positive lung cancers, focusing on differences in pretreatment co-occurring genetic alterations in circulating tumor DNA. This was a secondary analysis of the ELUCIDATOR study, a multicenter prospective observational study in Japan that assessed the mechanisms underlying resistance to osimertinib as a first-line treatment for advanced NSCLC with EGFR mutations. We compared the progression-free survival (PFS), overall survival (OS), and pretreatment co-occurring genetic alterations detected in plasma between patients with stages IVA (n = 83) and IVB disease (n = 84). Multivariate analysis of PFS and OS revealed that stage IVB was associated with a poor prognosis (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.36-3.04, p < 0.001, HR: 2.35, 95% CI: 1.45-3.90, p < 0.001, respectively). Pre-osimertinib treatment, significantly more TP53- (52.4% vs. 27.7%, p = 0.002), EGFR amplification- (58.3% vs. 23.2%, p < 0.001), and MET amplification-positive cases (22.6% vs. 7.2%, p = 0.008) were found among stage IVB than among stage IVA or lower cases. Patients with EGFR-positive NSCLC in stage IVB exhibited significantly shorter PFS and OS than those in earlier stages when treated with first-line osimertinib. The prevalence of baseline TP53 mutations, EGFR amplification, and MET amplification in plasma were significantly higher in stage IVB cases, implicating them in the worse outcomes of this group.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949026","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":"The analysis of molecular classification of pulmonary neuroendocrine tumors and relationship between YAP1 and efficacy.","authors":"Meihui Li, Xinyuan Wang, Jiali Gong, Hongyang Lu","doi":"10.1007/s10637-024-01492-6","DOIUrl":"https://doi.org/10.1007/s10637-024-01492-6","url":null,"abstract":"<p><p>A novel molecular classification for small cell lung cancer (SCLC) has been established utilizing the transcription factors achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NeuroD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). This classification was predicated on the transcription factors. Conversely, there is a paucity of information regarding the distribution of these markers in other subtypes of pulmonary neuroendocrine tumors (PNET). Clinical and survival data for PNET patients were gathered from January 2008 to December 2020. Immunohistochemical analysis was employed to evaluate the expression. The relationship between YAP1 expression and outcomes in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) was examined. Data from low-grade PNET patients who had previously undergone immunotherapy were retrospectively gathered and analyzed. The ASCL1 positive rate was markedly elevated in SCLC (7.1% vs. 60%; P < 0.001) and LCNEC patients (7.1% vs. 38.5%; P = 0.034) compared to PC patients. The YAP1-positive rate was elevated in LCNEC compared to SCLC (43.6% vs. 20%, P = 0.028) and pulmonary carcinoid (PC) patients (43.6% vs. 21.4%; P = 0.021). The DLL3-positive rate in SCLC patients was greater than in SCLC and PC patients (37.1% vs. 23.1% vs. 0%; P = 0.028, P = 0.021). A significant level of tumor heterogeneity was noted, with SCLC and LCNEC patients exhibiting markedly higher heterogeneity than PC patients (65.7% vs. 56.3% vs. 21.4%; P = 0.005, P = 0.025). In patients with LCNEC, YAP1 positivity exhibited no correlation with PD-L1 expression (17.1% vs. 45.7%, P = 0.518). Tumor heterogeneity was also noted in transformed SCLC, with no significant differences in the expression levels of transcription factors between transformed and traditional SCLC. In 13 LCNEC patients with a history of ICI application, YAP1 exhibited no significant effect on PFS (P = 0.331) or OS (P = 0.17) in the subgroup analysis of LCNEC patients. Among the 14 patients with low-grade PNET who underwent immunotherapy, the disease control rate was 85.7%. Patients with high-grade PNET have high levels of expression of ASCL1 and DLL3, whereas patients with LCNEC have high levels of expression of YAP1. With regard to the transcription factor level, it was found that patients with SCLC and LCNEC had a much higher degree of tumor heterogeneity than those with PC. In patients with LCNEC who were receiving monotherapy of ICIs or chemotherapy in combination with ICIs, the expression of YAP1 did not appear to have any clear impact on the prognosis. This is due to the limited sample size of the study, which requires additional investigation. When compared to the expression of TFs in regular SCLC, the expression of TFs in converted SCLC is comparable.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949028","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":"Efficacy and safety of multi-target tyrosine kinase inhibitor AL2846 combined with gemcitabine in pancreatic cancer.","authors":"Rui Liu, Zhi Ji, Xia Wang, Jiaqi Xin, Lila Zhu, Shaohua Ge, Le Zhang, Ming Bai, Tao Ning, Yuchong Yang, Hongli Li, Ting Deng, Yi Ba","doi":"10.1007/s10637-024-01485-5","DOIUrl":"https://doi.org/10.1007/s10637-024-01485-5","url":null,"abstract":"<p><p>Pancreatic cancer patients urgently need new treatments, and we explored the efficacy and safety of combination therapy with AL2846 and gemcitabine in pancreatic cancer patients. This was a single-arm, single-center, open-label phase I/IIa study (NCT06278493). The dose-escalation phase was designed to evaluate the maximum tolerated dose (MTD) of AL2846 combined with gemcitabine. One or two dose levels were chosen for the dose-expansion phase. Treatment continued until disease progression, intolerable toxicity, patient withdrawal, or at the investigators' discretion. The primary study endpoint is to evaluate the safety and MTD of AL2846 combined with gemcitabine. The secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and disease control rate (DCR). Between August 2018 and July 2021, 33 pancreatic cancer patients were enrolled in the study. A total of 15 patients were enrolled in the dose-escalation phase, and the MTD was not determined. Eventually 90 mg and 120 mg of AL2846 were chosen for the dose-expansion phase, in which 11 patients (90 mg) and 7 patients (120 mg) were administered. Treatment-related adverse events (TRAEs) of any grade were reported in 30 (90.91%) patients, and those of grade ≥ 3 were reported in 16 (48.48%) patients. The most frequently reported grade ≥ 3 TRAEs were thrombocytopenia (18.18%), neutropenia (12.12%), elevated γ-glutamyltransferase (6.06%), proteinuria (6.06%), and gastrointestinal hemorrhage (6.06%).The ORR was 6.06%, and the DCR was 72.73%. The median PFS was 3.71 months (95% CI: 3.38-4.11), and the median OS was 5.59 months (95% CI: 4.11-8.71). Gemcitabine and Al2846 combination therapy exhibited tolerable safety, but there was no improvement in efficacy over standard treatment. Further evaluation of this approach is still needed.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931704","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}