Investigational New Drugs最新文献

{"title":"Retraction Note: The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells.","authors":"Francesca De Iuliis, Ludovica Taglieri, Gerardo Salerno, Anna Giuffrida, Bernardina Milana, Sabrina Giantulli, Simone Carradori, Ida Silvestri, Susanna Scarpa","doi":"10.1007/s10637-024-01469-5","DOIUrl":"10.1007/s10637-024-01469-5","url":null,"abstract":"","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"601"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107520","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":"Depth of response and treatment outcomes of immune checkpoint inhibitor-based therapy in patients with advanced non-small cell lung cancer and high PD-L1 expression: An exploratory analysis of retrospective multicenter cohort.","authors":"Yusuke Tachibana, Kenji Morimoto, Tadaaki Yamada, Hayato Kawachi, Motohiro Tamiya, Yoshiki Negi, Yasuhiro Goto, Akira Nakao, Shinsuke Shiotsu, Keiko Tanimura, Takayuki Takeda, Asuka Okada, Taishi Harada, Koji Date, Yusuke Chihara, Isao Hasegawa, Nobuyo Tamiya, Yuki Katayama, Naoya Nishioka, Masahiro Iwasaku, Shinsaku Tokuda, Takashi Kijima, Koichi Takayama","doi":"10.1007/s10637-024-01467-7","DOIUrl":"10.1007/s10637-024-01467-7","url":null,"abstract":"<p><p>The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the significance of DpR is not elucidated. Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received ICI-monotherapy or ICI plus chemotherapy were retrospectively enrolled into this study. Treatment responses were grouped into DpR 'quartiles' by percentage of maximal tumor reduction (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, and Q4 =  ≥ 76%), and no tumor reduction (NTR). The association between DpR and survival rates were determined using hazard ratios (HR) generated by the Cox proportional hazards model. The Kaplan-Meier method was used to determine survival outcomes. A total of 349 patients were included, of which 214 and 135 patients received pembrolizumab monotherapy and ICI plus chemotherapy, respectively, as first-line treatments. The majority of the patients were male. All DpR quartiles, especially Q4, showed an association with progression-free survival (PFS)/overall survival (OS). In the Q4 cohort, patients who received pembrolizumab had a longer PFS than those who received ICI plus chemotherapy. High DpR was associated with longer PFS and OS, with a more pronounced effect observed with pembrolizumab monotherapy than with ICI plus chemotherapy.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"538-546"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017444","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 randomized phase 1 study of safety, tolerability, and pharmacokinetics of MK-1088, a novel dual adenosine receptor antagonist, in healthy adult participants.","authors":"Pranav Gupta, Manash Chatterjee, Yeonil Kim, Kathleen Deschamps, Lieselotte Lemoine, Kristien Van Dyck, Catherine Zhou Matthews, Sylvie Rottey, Aubrey Stoch, Eseng Lai","doi":"10.1007/s10637-024-01462-y","DOIUrl":"10.1007/s10637-024-01462-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"492-499"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912777","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}

{"title":"Design optimization of Fucoidan-coating Cationic Liposomes for enhance Gemcitabine delivery.","authors":"Epiphane K Silli, Zhenjiang Zheng, Xintao Zhou, Mengfei Li, Jiali Tang, Ruizhe Guo, Chunlu Tan, Ying Wang","doi":"10.1007/s10637-024-01455-x","DOIUrl":"10.1007/s10637-024-01455-x","url":null,"abstract":"<p><p>Obstacles facing chemotherapeutic drugs for cancers led scientists to load Gemcitabine (GEM) into nanocarriers like liposomes, known for their nontoxicity profile and targeting capacity. The liposomal nanostructures containing GEM were coated with Fucoidan (FU) due to its anti-tumor properties by targeting cancer cells. Thus four different cationic liposomes formulations were prepared by thin-film hydration method in optimal conditions: DOTAP (formulation A); DPPC/DOTAP (4:1 molar ratio, formulation B), DPPC/DMPC/DOTAP (4:1:1 molar ratio, formulation C) and DPPC/DMPC/DOTAP/DSPE-mPEG2000 (4:1:1:0.1 molar ratio, formulation D). They were studied to identify lipid-compositions offering effective GEM-entrapment and successful coating of FU on the liposome surface. Additional qualitative characteristics, such as particle size, polydispersity index, zeta potential, stability and in vitro drug release were then evaluated. Formulation C gave the best GEM-entrapment efficiency (EE) but formed aggregates when coated with FU, giving non-homogenous large size particles then not suitable for effective delivery. It was the same situation with formulation A and B. Only the formulation D showed a good GEM-EE (> 80%) and affinity by successful coating FU from three different algae species. The PEGylated formulation D coated of FU, with regard to storage stability and drug release studies, revealed to be a promising approach on design of optimal drug delivery system.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"518-530"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995734","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 multiple receptor tyrosine kinases with sitravatinib: A Phase 1b study in advanced renal cell carcinoma and castrate-resistant prostate cancer.","authors":"Shubham Pant, Byoung Chul Cho, Christos E Kyriakopoulos, Alexander Spira, Nizar Tannir, Theresa L Werner, Xiaohong Yan, Saskia Neuteboom, Richard Chao, Sanjay Goel","doi":"10.1007/s10637-024-01465-9","DOIUrl":"10.1007/s10637-024-01465-9","url":null,"abstract":"<p><p>Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also assessed. Overall, 48 patients (RCC n = 38, CRPC n = 10) received ≥ 1 dose of sitravatinib. Both cohorts were heavily pretreated (median number of prior systemic therapies: RCC cohort 3, CRPC cohort 6). In the RCC cohort, ORR was 25.9%, P = 0.015 (null hypothesis [ORR ≤ 10%] was rejected). Responses were durable (median duration 13.2 months). Median PFS was 9.5 months and median OS was 30.0 months. No objective responses were seen in the CRPC cohort; median PFS and OS were 5.8 months and 10.1 months, respectively. Across both cohorts, diarrhea (72.9%), fatigue (54.2%), and hypertension (52.1%) were the most frequent all-cause treatment-emergent adverse events (TEAEs). Diarrhea and vomiting (both, 6.3%) were the most frequent serious TEAEs considered related to study treatment. Sitravatinib demonstrated an acceptable safety profile and promising clinical activity in patients with clear cell RCC refractory to prior angiogenesis inhibitor therapy. Strong indicators for clinical activity were not seen in patients with CRPC and bone metastases. Clinical trial registration:ClinicalTrials.gov NCT02219711.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"547-558"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017445","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}

{"title":"Advancements of prodrug technologies for enhanced drug selectivity in pharmacotherapies.","authors":"Helin Li, Wenjing Zhang, Qiu Meng, Qi Shuai","doi":"10.1007/s10637-024-01460-0","DOIUrl":"10.1007/s10637-024-01460-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"590-600"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971105","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":"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":"<p><p>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.</p>","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}

{"title":"Broad-spectrum anti-cancer activity of fused human arginase variants.","authors":"Yenisetti Rajendra Prasad, J Anakha, Snehal Sainath Jawalekar, Abhay H Pande","doi":"10.1007/s10637-024-01466-8","DOIUrl":"10.1007/s10637-024-01466-8","url":null,"abstract":"<p><p>The rapid increase in cancer cases worldwide necessitates the development of novel therapeutic approaches. Therapies targeting cancer's altered metabolism, especially those that deplete critical amino acids, have emerged as promising ones, some of which are already being used in clinical practice and many others are under development. This study reports the anti-cancer activity of two novel fused human arginase I (FHA) variants, FHA-3 and FHA-12, assessed using the NCI-60 human tumor cell line panel. Both variants have demonstrated a range of potencies in a single-dose assay (10 µM), but FHA-3 was found to be more potent with significant growth inhibition in most tested cell lines. To calculate 50% growth inhibition (GI₅₀), FHA-3 was further evaluated in a five-dose assay, where notable anti-cancer activity was observed across the nine cancer types of the NCI-60 panel. Our results demonstrated the broad-spectrum anti-cancer activity of novel FHA variants, with FHA-3 being the most potent. Further studies elucidating its efficacy in animal models will help explore its therapeutic potential.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"531-537"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004236","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 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":"<p>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.</p>","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}

{"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":"<p>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.</p>","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}