Investigational New Drugs最新文献_第7页

Treatment response to durvalumab plus tremelimumab after progression with previous immune checkpoint inhibitor in unresectable hepatocellular carcinoma. 无法切除的肝细胞癌患者在使用前一种免疫检查点抑制剂治疗进展后，对durvalumab加tremelimumab的治疗反应。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-08-30 DOI: 10.1007/s10637-024-01470-y

Nami Mori, Nobuharu Tamaki, Shintaro Takaki, Keiji Tsuji, Toshifumi Tada, Shinichiro Nakamura, Hironori Ochi, Toshie Mashiba, Masao Doisaki, Hiroyuki Marusawa, Haruhiko Kobashi, Hideki Fujii, Chikara Ogawa, Michiko Nonogi, Hirotaka Arai, Yasushi Uchida, Naohito Urawa, Ryoichi Narita, Takehiro Akahane, Masahiko Kondo, Yutaka Yasui, Kaoru Tsuchiya, Namiki Izumi, Masayuki Kurosaki

{"title":"Treatment response to durvalumab plus tremelimumab after progression with previous immune checkpoint inhibitor in unresectable hepatocellular carcinoma.","authors":"Nami Mori, Nobuharu Tamaki, Shintaro Takaki, Keiji Tsuji, Toshifumi Tada, Shinichiro Nakamura, Hironori Ochi, Toshie Mashiba, Masao Doisaki, Hiroyuki Marusawa, Haruhiko Kobashi, Hideki Fujii, Chikara Ogawa, Michiko Nonogi, Hirotaka Arai, Yasushi Uchida, Naohito Urawa, Ryoichi Narita, Takehiro Akahane, Masahiko Kondo, Yutaka Yasui, Kaoru Tsuchiya, Namiki Izumi, Masayuki Kurosaki","doi":"10.1007/s10637-024-01470-y","DOIUrl":"10.1007/s10637-024-01470-y","url":null,"abstract":"Although immune checkpoint inhibitors (ICI) are used for unresectable hepatocellular carcinoma (HCC), it is unclear whether sequential ICI treatment-durvalumab plus tremelimumab (DT) after progression on atezolizumab plus bevacizumab (AB)-is effective for HCC. In this nationwide multicenter study, we aimed to investigate the effect of DT treatment based on the timing of treatment. A total of 85 patients receiving DT treatment were enrolled. The primary endpoint is treatment response at week 8 among patients receiving first-line DT treatment, those receiving second-line or later treatment without prior AB therapy, and those receiving second-line or later treatment with prior AB therapy. Objective response rates (ORRs) in patients with first-line treatment, second-line treatment without AB, and second-line treatment with prior AB were 44%, 54%, and 5%, respectively (p < 0.001). Similarly, disease control rates (DCRs) were 69%, 91%, and 26%, respectively (p < 0.001). ORR and DCR were significantly lower in patients with prior AB treatment. Progression free survival (PFS) was significantly shortened in patients receiving second-line therapy following prior AB treatment and an adjusted hazard ratio (95% confidence interval) in those patients for PFS, using first-line therapy as a reference, was 2.35 (1.1-5.1, p = 0.03). In conclusion, the impact of DT sequencing following AB treatment was limited. However, even after second-line treatment, the treatment effect can be equivalent to that of first-line treatment in cases with no history of AB treatment. Thus, prior treatment history should be taken into account when initiating DT treatment.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"559-565"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107521","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}

引用次数: 0

Broad-spectrum anti-cancer activity of fused human arginase variants. 融合人精氨酸酶变体的广谱抗癌活性。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-08-20 DOI: 10.1007/s10637-024-01466-8

Yenisetti Rajendra Prasad, J Anakha, Snehal Sainath Jawalekar, Abhay H Pande

引用次数: 0

A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors ERK抑制剂MK-8353联合pembrolizumab治疗晚期实体瘤患者的1b期研究

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2024-09-14 DOI: 10.1007/s10637-024-01461-z

Nehal J. Lakhani, Howard Burris, Wilson H. Miller, Mo Huang, Lin-Chi Chen, Lillian L. Siu

{"title":"A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors","authors":"Nehal J. Lakhani, Howard Burris, Wilson H. Miller, Mo Huang, Lin-Chi Chen, Lillian L. Siu","doi":"10.1007/s10637-024-01461-z","DOIUrl":"https://doi.org/10.1007/s10637-024-01461-z","url":null,"abstract":"Combining a checkpoint inhibitor with an inhibitor of extracellular signal-regulated kinase (ERK) may result in synergistic antitumor activity. We evaluated MK-8353, an ERK1 and ERK2 inhibitor, plus pembrolizumab in a phase 1b study in patients with advanced solid tumors. This open-label, nonrandomized, dose-escalation study (NCT02972034) enrolled adults with advanced solid tumors previously treated with 1‒5 prior lines of therapy. MK-8353 was administered orally in combination with pembrolizumab 200 mg every 3 weeks as follows: twice daily (arm A; MK-8353 50‒350 mg), once daily (arm B; MK-8353 50‒600 mg), or once daily every other week (arm C; MK-8353 50‒300 mg). The primary objective was evaluation of safety via occurrence of dose-limiting toxicities (DLTs). A secondary objective was objective response by RECIST v1.1 per investigator assessment. Among 110 evaluable patients (arm A, n = 22; arm B, n = 50; arm C, n = 38), median age was 58.0 (range, 35‒79) years and 50% had received 1 or 2 prior lines of therapy. DLTs occurred in 19 patients (n = 6 [27%], n = 8 [16%], and n = 5 [13%], respectively); the most frequent was grade 3 maculopapular rash (n = 15). Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"16 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255690","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}

引用次数: 0

Clinical characteristics, treatment, and outcomes of nivolumab induced immune thrombocytopenia 尼伐单抗诱发免疫性血小板减少症的临床特征、治疗和预后

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2024-09-12 DOI: 10.1007/s10637-024-01472-w

Liping Peng, Zhaoquan Wu, Wei Sun, Chunjiang Wang

{"title":"Clinical characteristics, treatment, and outcomes of nivolumab induced immune thrombocytopenia","authors":"Liping Peng, Zhaoquan Wu, Wei Sun, Chunjiang Wang","doi":"10.1007/s10637-024-01472-w","DOIUrl":"https://doi.org/10.1007/s10637-024-01472-w","url":null,"abstract":"Immune thrombocytopenia (ITP) represents an uncommon hematological side effect associated with nivolumab, and its distinct clinical attributes remain poorly defined. This research aimed to explore the clinical manifestations and outcomes of ITP induced by nivolumab. Reports on nivolumab induced ITP up to April 30, 2024, were collected for retrospective analysis. The study involved 34 patients with a median age of 67 years (range 32, 82). The onset of ITP varied from 10 to 100 days post initial dosage, with a median onset at 70 days. The majority of patients exhibited no symptoms, with only 23.5% experiencing clinically significant bleeding and 11.8% facing non-clinically significant bleeding. The median platelet count was 12 × 109/L (range 0, 115), with 67.6% of patients having platelet levels below 25 × 109/L. Bone marrow biopsy revealed mainly elevated megakaryocytes. Platelet-associated IgG levels were elevated with a median of 210 ng/107 cells (range 73, 1130). Subsequent interventions, which included cessation of nivolumab, administration of systemic corticosteroids, intravenous immunoglobulin therapy, a thrombopoietin receptor agonist, platelet transfusion, and rituximab treatment, resulted in 82.4% of subjects achieving normalized platelet counts, whereas 5.9% passed away due to ITP. ITP is a rare life-threatening immune-related adverse event and necessitates close monitoring. Systemic steroids are the primary treatment for ITP, while intravenous immunoglobulin, thrombopoietin receptor agonist and rituximab are other options.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"280 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142213298","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}

引用次数: 0

A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors 在晚期实体瘤患者中开展的普卢巴林和吉西他滨安全性和有效性 I 期临床试验

IF 3.4 3区医学

Investigational New Drugs Pub Date : 2024-08-03 DOI: 10.1007/s10637-024-01458-8

Mohammad H. Ghalib, Mariano Provencio Pulla, Maria J. De Miguel Luken, Virginia Calvo de Juan, Imran Chaudhary, M Bakri Hammami, Sindhu Vikash, Radhashree Maitra, Sara Martinez, Carmen Kahatt, Sonia Extremera, Salvador Fudio, Sanjay Goel

{"title":"A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors","authors":"Mohammad H. Ghalib, Mariano Provencio Pulla, Maria J. De Miguel Luken, Virginia Calvo de Juan, Imran Chaudhary, M Bakri Hammami, Sindhu Vikash, Radhashree Maitra, Sara Martinez, Carmen Kahatt, Sonia Extremera, Salvador Fudio, Sanjay Goel","doi":"10.1007/s10637-024-01458-8","DOIUrl":"https://doi.org/10.1007/s10637-024-01458-8","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Summary</h3>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.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":"98 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141886836","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}

引用次数: 0

Effect of PAWI-2 on pancreatic cancer stem cell tumors. PAWI-2 对胰腺癌干细胞肿瘤的影响

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-08-01 Epub Date: 2024-05-25 DOI: 10.1007/s10637-024-01447-x

John R Cashman, Emily A Cashman

{"title":"Effect of PAWI-2 on pancreatic cancer stem cell tumors.","authors":"John R Cashman, Emily A Cashman","doi":"10.1007/s10637-024-01447-x","DOIUrl":"10.1007/s10637-024-01447-x","url":null,"abstract":"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.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"353-360"},"PeriodicalIF":3.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093628","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}

引用次数: 0

Radiosensitization effect of quinoline-indole-schiff base derivative 10E on non-small cell lung cancer cells in vitro and in tumor xenografts. 喹啉-吲哚-席夫碱衍生物 10E 对体外和肿瘤异种移植非小细胞肺癌细胞的放射增敏效应

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-08-01 Epub Date: 2024-06-17 DOI: 10.1007/s10637-024-01451-1

Hongwei Liu, Qianqian Wang, Wanying Lan, Duanya Liu, Jiangang Huang, Jie Yao

{"title":"Radiosensitization effect of quinoline-indole-schiff base derivative 10E on non-small cell lung cancer cells in vitro and in tumor xenografts.","authors":"Hongwei Liu, Qianqian Wang, Wanying Lan, Duanya Liu, Jiangang Huang, Jie Yao","doi":"10.1007/s10637-024-01451-1","DOIUrl":"10.1007/s10637-024-01451-1","url":null,"abstract":"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.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"405-417"},"PeriodicalIF":3.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330953","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}

引用次数: 0

Auger emitter in combination with Olaparib suppresses tumor growth via promoting antitumor immune responses in pancreatic cancer. 奥杰尔发射器与奥拉帕利（Olaparib）联用可通过促进胰腺癌患者的抗肿瘤免疫反应抑制肿瘤生长。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-08-01 Epub Date: 2024-06-28 DOI: 10.1007/s10637-024-01454-y

Yanqi Zhong, Heng Zhang, Peng Wang, Jing Zhao, Yuxi Ge, Zongqiong Sun, Zi Wang, Jie Li, Shudong Hu

{"title":"Auger emitter in combination with Olaparib suppresses tumor growth via promoting antitumor immune responses in pancreatic cancer.","authors":"Yanqi Zhong, Heng Zhang, Peng Wang, Jing Zhao, Yuxi Ge, Zongqiong Sun, Zi Wang, Jie Li, Shudong Hu","doi":"10.1007/s10637-024-01454-y","DOIUrl":"10.1007/s10637-024-01454-y","url":null,"abstract":"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.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"442-453"},"PeriodicalIF":3.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468010","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}

引用次数: 0

Liposomal irinotecan (HR070803) in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors: a phase 1b dose-escalation and expansion study. 脂质体伊立替康（HR070803）联合 5-氟尿嘧啶和白消安治疗晚期实体瘤患者：1b 期剂量递增和扩展研究。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-08-01 Epub Date: 2024-07-22 DOI: 10.1007/s10637-024-01442-2

Dongmei Ji, Weina Shen, Ting Li, Huan Wang, Jianling Bai, Junning Cao, Xichun Hu

{"title":"Liposomal irinotecan (HR070803) in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors: a phase 1b dose-escalation and expansion study.","authors":"Dongmei Ji, Weina Shen, Ting Li, Huan Wang, Jianling Bai, Junning Cao, Xichun Hu","doi":"10.1007/s10637-024-01442-2","DOIUrl":"10.1007/s10637-024-01442-2","url":null,"abstract":"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.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"462-470"},"PeriodicalIF":3.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11327190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical characteristics, treatment and outcome of pembrolizumab-induced acute pancreatitis. 彭博利珠单抗诱发急性胰腺炎的临床特征、治疗和预后。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-08-01 Epub Date: 2024-06-03 DOI: 10.1007/s10637-024-01452-0

Panpan Luo, Yuge Guo, Yang He, Chunjiang Wang

{"title":"Clinical characteristics, treatment and outcome of pembrolizumab-induced acute pancreatitis.","authors":"Panpan Luo, Yuge Guo, Yang He, Chunjiang Wang","doi":"10.1007/s10637-024-01452-0","DOIUrl":"10.1007/s10637-024-01452-0","url":null,"abstract":"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.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"369-375"},"PeriodicalIF":3.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199838","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}

引用次数: 0