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Investigational New Drugs

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https://read.qxmd.com/read/31102120/assessment-of-the-cytotoxic-effects-of-aporphine-prototypes-on-head-and-neck-cancer-cells
#1
Dorival Mendes Rodrigues-Junior, Nicolie Melanie de Almeida Pontes, Gabriela Estrela de Albuquerque, Viviane Carlin, Givago Prado Perecim, Cristiano Raminelli, André Luiz Vettore
Purpose Among alkaloids, abundant secondary metabolites in plants, aporphines constitute a class of compounds with interesting biological activities, including anticancer effects. The present study evaluated the anticancer activities of 14 substances, including four aporphine derivatives acquired through the biomonitoring of (±)-apomorphine hydrochloride total synthesis from 2-phenethylamine and 3,4-dimethoxybenzaldehyde against head and neck squamous cell carcinoma (HNSCC). Methods The cytotoxic effects of compounds against a panel of HNSCC cell lines were determined by PrestoBlue cell viability assay, while the genotoxicity of substances was evaluated by micronucleus test...
May 17, 2019: Investigational New Drugs
https://read.qxmd.com/read/31102119/preclinical-activity-and-a-pilot-phase-i-study-of-pacritinib-an-oral-jak2-flt3-inhibitor-and-chemotherapy-in-flt3-itd-positve-aml
#2
Jae Yoon Jeon, Qiuhong Zhao, Daelynn R Buelow, Mitch Phelps, Alison R Walker, Alice S Mims, Sumithira Vasu, Gregory Behbehani, James Blachly, William Blum, Rebecca B Klisovic, John C Byrd, Ramiro Garzon, Sharyn D Baker, Bhavana Bhatnagar
Activating FLT3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has in vitro activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations. Therefore, we conducted a phase I study of pacritinib in combination with chemotherapy in AML patients with FLT3 mutations to determine the pharmacokinetics and preliminary toxicity and clinical activity. Pacritinib was administered at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin (cohort A) or with decitabine induction (cohort B)...
May 17, 2019: Investigational New Drugs
https://read.qxmd.com/read/31102118/cardamonin-a-natural-chalcone-reduces-5-fluorouracil-resistance-of-gastric-cancer-cells-through-targeting-wnt-%C3%AE-catenin-signal-pathway
#3
Gaochao Hou, Xiang Yuan, Yi Li, Gaoyu Hou, Xianli Liu
Objectives Cardamonin (CD), an active chalconoid, has been extensively studied in a wide variety of human tumors. However, the effects and underlying mechanism of cardamonin on 5-fluorouracil (5-FU)-resistant gastric cancer (GC) remain largely unclear. This study aimed to investigate the antitumor effects of cardamonin on 5-FU-resistant GC cells and explore the molecular mechanisms underlying its therapeutic potential. Methods The antitumor activities of cardamonin, 5-FU and their combination against BGC-823 and BGC-823/5-FU cells were determined using cytotoxicity assay, flow cytometry-based cell cycle analysis and Annexin V apoptosis assay...
May 17, 2019: Investigational New Drugs
https://read.qxmd.com/read/31087223/zelnorm-an-agonist-of-5-hydroxytryptamine-4-receptor-acts-as-a-potential-antitumor-drug-by-targeting-jak-stat3-signaling
#4
Lei Zhang, Qiaoling Song, Xinxin Zhang, Li Li, Ximing Xu, Xiaohan Xu, Xiaoyu Li, Zhuoya Wang, Yuxi Lin, Xin Li, Mengyuan Li, Fan Su, Xin Wang, Peiju Qiu, Huashi Guan, Yu Tang, Wenfang Xu, Jinbo Yang, Chenyang Zhao
The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor...
May 14, 2019: Investigational New Drugs
https://read.qxmd.com/read/31087222/expression-of-the-pten-foxo3a-plzf-signalling-pathway-in-pancreatic-cancer-and-its-significance-in-tumourigenesis-and-progression
#5
Qiubo Zhang, Xuanna Li, Yaqing Li, Shaojie Chen, Xiaoling Shen, Xianwen Dong, Yufei Song, Xuesong Zhang, Kaihong Huang
Pancreatic cancer (PC) is one of the most lethal gastrointestinal malignancies. The PTEN/AKT signalling pathway is closely related to the tumourigenesis and progression of PC. The downstream effectors, FOXO3a, PLZF and VEGF, are reported to be involved in angiogenesis, lymph node metastasis and poor survival in PC. By using tissue microarrays and immunohistochemistry, we found, that PTEN, FOXO3a and PLZF expression was significantly decreased in PC specimens compared with that in chronic pancreatitis (CP) specimens, while VEGF expression was significantly increased...
May 14, 2019: Investigational New Drugs
https://read.qxmd.com/read/31076964/identification-of-a-3-3-difluorinated-tetrahydropyridinol-compound-as-a-novel-antitumor-agent-for-hepatocellular-carcinoma-acting-via-cell-cycle-arrest-through-disturbing-cdk7-mediated-phosphorylation-of-cdc2
#6
Wu Bi, Ji-Chang Xiao, Rui-Jie Liu, Liu-Ying Zhou, Sai Zhang, Mei Yang, Peng-Fei Zhang
Tetrahydropyridinol derivatives were recently reported to exhibit good biological activities, and the incorporation of fluorine into organic molecules may have profound effects on their physical and biological properties. Therefore, we investigated the anticancer activities of six fluorinated tetrahydropyridinol derivatives that we synthesized previously. We found that only one compound, 3,3-difluoro-2,2-dimethyl-1,6-diphenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol, showed significant antiproliferative activity on human hepatocellular carcinoma HepG2 and HMCCLM3 cells (the IC50 values were 21...
May 11, 2019: Investigational New Drugs
https://read.qxmd.com/read/31076963/pam-3-csk-4-a-tlr2-ligand-induces-differentiation-of-glioblastoma-stem-cells-and-confers-susceptibility-to-temozolomide
#7
Javier Megías, Alba Martínez, Teresa San-Miguel, Rosario Gil-Benso, Lisandra Muñoz-Hidalgo, David Albert-Bellver, Amara Carratalá, Daniel Gozalbo, Concha López-Ginés, María Luisa Gil, Miguel Cerdá-Nicolás
Glioblastoma multiforme (GBM) is the most aggressive human brain tumor, and GBM stem cells (GSC) may be responsible for its recurrence and therapeutic resistance. Toll-like receptors (TLRs), which recognize multiple ligands (endogenous and pathogen-associated) and trigger the immune response of mature immune cells, are also expressed by hematopoietic stem and progenitor cells, where their activation results in the differentiation of these cells into myeloid cells. Since TLR expression has been recently described in neural cells, including neural stem cells, we studied TLR expression by GSCs and the effect of stimulation by TLR ligands on promoting GSC differentiation into mature GBM cells...
May 11, 2019: Investigational New Drugs
https://read.qxmd.com/read/31065954/a-phase-ib-study-of-gsk3052230-an-fgf-ligand-trap-in-combination-with-pemetrexed-and-cisplatin-in-patients-with-malignant-pleural-mesothelioma
#8
Emilie M J van Brummelen, Evgeny Levchenko, Manuel Dómine, Dean A Fennell, Hedy L Kindler, Santiago Viteri, Shirish Gadgeel, Pilar Garrido López, Vladimir Kostorov, Daniel Morgensztern, Sergey Orlov, Marjorie G Zauderer, Johan F Vansteenkiste, Katherine Baker-Neblett, James Vasquez, Xiaowei Wang, David I Bellovin, Jan H M Schellens, Li Yan, Ionel Mitrica, M Phillip DeYoung, José Trigo
Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD)...
May 7, 2019: Investigational New Drugs
https://read.qxmd.com/read/31041575/a-phase-1-study-of-oral-asp5878-a-selective-small-molecule-inhibitor-of-fibroblast-growth-factor-receptors-1-4-as-a-single-dose-and-multiple-doses-in-patients-with-solid-malignancies
#9
Noboru Yamamoto, Baek-Yeol Ryoo, Bhumsuk Keam, Masatoshi Kudo, Chia-Chi Lin, Futoshi Kunieda, Howard A Ball, Diarmuid Moran, Kanji Komatsu, Kentaro Takeda, Musashi Fukuda, Junji Furuse, Satoshi Morita, Toshihiko Doi
ASP5878 is a selective small-molecule inhibitor of fibroblast growth factor receptors (FGFRs). This study investigated safety, tolerability, and antitumor effect of single and multiple oral doses of ASP5878 in patients with solid tumors. This phase 1, open label, first-in-human study comprised dose-escalation and dose-expansion parts. Primary objectives of the dose-escalation part were to identify the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended dose of ASP5878 for the dose-expansion part...
April 30, 2019: Investigational New Drugs
https://read.qxmd.com/read/31037562/randomized-phase-ii-trial-of-neoadjuvant-everolimus-in-patients-with-high-risk-localized-prostate-cancer
#10
Vadim S Koshkin, Maria C Mir, Pedro Barata, Anita Gul, Ruby Gupta, Andrew J Stephenson, Jihad Kaouk, Ryan Berglund, Cristina Magi-Galluzzi, Eric A Klein, Robert Dreicer, Jorge A Garcia
Background Despite definitive local therapy, patients with high-risk prostate cancer have a significant risk for local and distant failure. To date, no systemic therapy given prior to surgery has been shown to improve outcomes. The phosphatidilinositol 3-kinase/AKT/mTOR pathway is commonly dysregulated in men with prostate cancer. We sought to determine the clinical efficacy and safety of the mTOR/TORC1 inhibitor everolimus in men with high-risk prostate cancer undergoing radical prostatectomy. Methods This is a randomized phase II study of everolimus at two different doses (5 and 10 mg daily) given orally for 8 weeks before radical prostatectomy in men with high-risk prostate cancer...
April 30, 2019: Investigational New Drugs
https://read.qxmd.com/read/31032525/correction-to-sphingadienes-show-therapeutic-efficacy-in-neuroblastoma-in-vitro-and-in-vivo-by-targeting-the-akt-signaling-pathway
#11
Piming Zhao, Ana E Aguilar, Joanna Y Lee, Lucy A Paul, Jung H Suh, Latika Puri, Meng Zhang, Jennifer Beckstead, Andrzej Witkowski, Robert O Ryan, Julie D Saba
The authors would like to note an omission of disclosure in this paper. Author JDS is cofounder, equity-holder, and consultant of GILTRx Therapeutics.
April 29, 2019: Investigational New Drugs
https://read.qxmd.com/read/31030314/anticancer-activity-apoptosis-and-a-structure-activity-analysis-of-a-series-of-1-4-naphthoquinone-2-3-bis-sulfides
#12
Kevin W Wellington, Natasha I Kolesnikova, Vincent Hlatshwayo, Sourav T Saha, Mandeep Kaur, Lesetja R Motadi
We have previously reported on the synthesis of 1,4-naphthoquinone-sulfides and in this investigation we report on their anticancer activity against 6 human cancer cell lines to evaluate their cytostatic effects. The 1,4-naphthoquinone-2,3-bis-sulfides were most effective against melanoma (UACC62) (GI50  = 6.5-10 μM) and prostate (PC3) (GI50  = 5.51-8.53 μM) cancer cell lines. They exhibited better cytostatic effects than etoposide (GI50  = 0.56-36.62 μM), parthenolide (GI50  = 3.58-25...
April 27, 2019: Investigational New Drugs
https://read.qxmd.com/read/31028664/clinical-pharmacokinetics-and-pharmacodynamics-of-ivosidenib-an-oral-targeted-inhibitor-of-mutant-idh1-in-patients-with-advanced-solid-tumors
#13
Bin Fan, Ingo K Mellinghoff, Patrick Y Wen, Maeve A Lowery, Lipika Goyal, William D Tap, Shuchi S Pandya, Erika Manyak, Liewen Jiang, Guowen Liu, Tara Nimkar, Camelia Gliser, Molly Prahl Judge, Sam Agresta, Hua Yang, David Dai
Background Mutant isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma. We explored the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ivosidenib in these populations. Methods Ivosidenib was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles; 168 patients received ≥1 dose within the range 100 mg BID to 1200 mg QD...
April 26, 2019: Investigational New Drugs
https://read.qxmd.com/read/31028663/the-metronomic-all-oral-devec-is-an-effective-schedule-in-elderly-patients-with-diffuse-large-b-cell-lymphoma
#14
M Christina Cox, Sabrina Pelliccia, Luigi Marcheselli, Roberta Battistini, Annalisa Arcari, Paola Anticoli Borza, Caterina Patti, Ivana Casaroli, Francesca di Landro, Arianna Di Napoli, Francesca Fabbri, Matteo Caridi, Agostino Tafuri, Guido Bocci, Gerardo Musuraca
Metronomic-chemotherapy (M-CHT) has been rarely assessed in non-Hodgkin-lymphoma (NHL). Therefore, in 2011 we started experimenting a new all-oral M-CHT schedule termed DEVEC (Deltacortene®, etoposide, vinorelbine, cyclophosphamide, +/-Rituximab) in diffuse-large-B-cell lymphoma (DLBCL) patients. Methods Patients with stage Ib-IV were enrolled as follows: 1) treatment-naïve, frail ≥65y, or unfit ≥85y; and 2) relapsed/refractory (R/R) ≥55y. Data were prospectively collected from six Italian centres and compared for efficacy to two reference groups, treated with established iv Rituximab-CHT in 1st and 2nd line respectively...
April 26, 2019: Investigational New Drugs
https://read.qxmd.com/read/31025237/correction-to-eribulin-trastuzumab-and-pertuzumab-as-first-line-therapy-for-patients-with-her2-positive-metastatic-breast-cancer-a-phase-ii-multicenter-collaborative-open-label-single-arm-clinical-trial
#15
Kenichi Inoue, Jun Ninomiya, Tsuyoshi Saito, Katsuhiko Okubo, Takashi Nakakuma, Hirofumi Yamada, Kei Kimizuka, Tohru Higuchi
The authors would like to note the replacement of Fig. 2b, for which Fig. 2a was placed erringly, with appropriate Fig. 2b.
April 25, 2019: Investigational New Drugs
https://read.qxmd.com/read/31020609/phase-i-study-of-the-anti-heparin-binding-epidermal-growth-factor-like-growth-factor-antibody-u3-1565-with-cetuximab-in-patients-with-cetuximab-or-panitumumab-resistant-metastatic-colorectal-cancer
#16
Takako Eguchi Nakajima, Narikazu Boku, Ayako Doi, Hiroyuki Arai, Takuro Mizukami, Yoshiki Horie, Naoki Izawa, Mami Hirakawa, Takashi Ogura, Takashi Tsuda, Yu Sunakawa
KRAS wild-type colorectal cancers initially responsive to anti-endothelial growth factor receptor (EGFR) antibodies [cetuximab (Cetu)/panitumumab (Pani)] develop acquired resistance. Overexpression of EGFR ligands such as heparin-binding EGF-like growth factor (HB-EGF) may be one resistance mechanism. This phase I study of U3-1565, anti-HB-EGF antibody, and Cetu combination therapy enrolled patients with KRAS wild-type metastatic colorectal cancer who had received two ≤ regimens with fluoropyrimidine, oxaliplatin, irinotecan, and Cetu/Pani and had disease progression on Cetu/Pani...
April 24, 2019: Investigational New Drugs
https://read.qxmd.com/read/31020608/phase-ib-study-of-the-mek-inhibitor-cobimetinib-gdc-0973-in-combination-with-the-pi3k-inhibitor-pictilisib-gdc-0941-in-patients-with-advanced-solid-tumors
#17
Geoffrey I Shapiro, Patricia LoRusso, Eunice Kwak, Susan Pandya, Charles M Rudin, Carla Kurkjian, James M Cleary, Mary Jo Pilat, Suzanne Jones, Alex de Crespigny, Jill Fredrickson, Luna Musib, Yibing Yan, Matthew Wongchenko, Hsin-Ju Hsieh, Mary R Gates, Iris T Chan, Johanna Bendell
Purpose We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study. Experimental Design Patients with advanced solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off ("21/7"); (2) intermittent cobimetinib and 21/7 pictilisib ("intermittent"); or (3) both agents once-daily for 7-days-on 7-days-off ("7/7"). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively...
April 24, 2019: Investigational New Drugs
https://read.qxmd.com/read/31020607/correction-to-phase-ib-ii-study-of-gemcitabine-nab-paclitaxel-and-pembrolizumab-in-metastatic-pancreatic-adenocarcinoma
#18
Glen J Weiss, Lisa Blaydorn, Julia Beck, Kirsten Bornemann-Kolatzki, Howard Urnovitz, Ekkhard Schütz, Vivek Khemka
The authors would like to note an error in Figures 1 and 2 of this paper. The graph in Figure 1 incorrectly reflected the overall survival (OS), when it should have displayed the progression-free survival (PFS). The caption and median PFS values were correct.
April 24, 2019: Investigational New Drugs
https://read.qxmd.com/read/30993588/a-preclinical-evaluation-of-thiostrepton-a-natural-antibiotic-in-nasopharyngeal-carcinoma
#19
Yen-Bin Hsu, Ming-Chin Lan, Yu-Lun Kuo, Chi-Ying F Huang, Ming-Ying Lan
Background Thiostrepton, a natural antibiotic, has recently been shown to be a potential anticancer drug for certain cancers, but its study in nasopharyngeal carcinoma (NPC) is still limited. The aims of this study were to investigate the anticancer effect of thiostrepton on NPC cells and to explore its underlying mechanism. Methods The effects of thiostrepton on the proliferation, migration, and invasion of NPC cells were investigated by a WST-1 assay, wound healing assay, and cell invasion assay, respectively...
April 16, 2019: Investigational New Drugs
https://read.qxmd.com/read/30993587/a-phase-2-open-label-study-of-brentuximab-vedotin-in-patients-with-cd30-expressing-solid-tumors
#20
Jeffrey P Sharman, Jennifer J Wheler, Lawrence Einhorn, Afshin Dowlati, Geoffrey I Shapiro, John Hilton, John M Burke, Tanya Siddiqi, Nancy Whiting, Shadia I Jalal
Purpose Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate used in the treatment of several types of lymphomas. Expression of the target antigen has also been reported on a variety of malignant tumors of nonlymphoid origin. This phase 2, open-label study evaluated the safety and antitumor activity of BV in patients with CD30-expressing nonlymphomatous malignancies. Methods Patients were dosed with 1.8 or 2.4 mg/kg BV once every three weeks. Antitumor activity was assessed at Cycles 2, 4, and every 4 cycles thereafter...
April 16, 2019: Investigational New Drugs
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