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Investigational New Drugs

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https://www.readbyqxmd.com/read/29998365/phase-ib-trial-combining-capecitabine-erlotinib-and-bevacizumab-in-pancreatic-adenocarcinoma-rebeca-trial
#1
Christian Dittrich, Robert Königsberg, Martina Mittlböck, Klaus Geissler, Azra Sahmanovic-Hrgovcic, Johannes Pleiner-Duxneuner, Martin Czejka, Philipp Buchner
Background Purpose of this phase Ib trial was to establish the maximum tolerable dose (MTD) of capecitabine and to escalate the dosages of erlotinib and bevacizumab to determine the recommended phase II dose (RP2D) in patients with advanced/metastatic pancreatic adenocarcinoma not pretreated for metastatic disease. Methods Starting doses were capecitabine 500 mg/m2 bid orally continuously, erlotinib 100 mg orally daily, and bevacizumab 5 mg/kg intravenously q 2 weeks. Dose escalation was performed according to a 3 + 3 design for capecitabine until MTD, for erlotinib and bevacizumab until the maximum doses registered by applying a substance-related, toxicity-based scheme accompanied by pharmacokinetic analysis...
July 12, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29998364/the-marine-natural-product-scalarin-inhibits-the-receptor-for-advanced-glycation-end-products-rage-and-autophagy-in-the-panc-1-and-mia-paca-2-pancreatic-cancer-cell-lines
#2
Esther Amalia Guzmán, Tara Peterson Pitts, Maria Cristina Diaz, Amy Elizabeth Wright
Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Although combination therapies are showing improvements in treatment, the survival rate for pancreatic cancer five years post diagnosis is only 8%, stressing the need for new treatments. The receptor for advanced glycation end products (RAGE) has recently emerged as a chemotherapeutic target in KRAS driven pancreatic cancers both for treatment and in chemoprevention...
July 12, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29995287/phase-i-study-of-resminostat-an-hdac-inhibitor-combined-with-s-1-in-patients-with-pre-treated-biliary-tract-or-pancreatic-cancer
#3
Masafumi Ikeda, Izumi Ohno, Hideki Ueno, Shuichi Mitsunaga, Yusuke Hashimoto, Takuji Okusaka, Shunsuke Kondo, Mitsuhito Sasaki, Yasunari Sakamoto, Hideaki Takahashi, Rina Hara, Shingo Kobayashi, Osamu Nakamura, Chigusa Morizane
Resminostat is an oral hydroxamate inhibitor of class I, IIb, and IV histone deacetylases. S-1 is widely used to treat biliary tract cancer and pancreatic cancer in Japan. We performed a phase I study of resminostat combined with S-1 as second-line or later therapy in Japanese patients with biliary tract or pancreatic cancer. A total of 27 patients were enrolled. We determined the optimal regimen for resminostat/S-1 therapy in part 1, and investigated its safety and efficacy in part 2. In part 1, 17 patients were enrolled...
July 11, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29995286/a-phase-1b-study-of-transforming-growth-factor-beta-receptor-i-inhibitor-galunisertib-in-combination-with-sorafenib-in-japanese-patients-with-unresectable-hepatocellular-carcinoma
#4
Masafumi Ikeda, Manabu Morimoto, Masaomi Tajimi, Koichi Inoue, Karim A Benhadji, Michael M F Lahn, Daisuke Sakai
Background Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galunisertib 80 mg or 150 mg was administered orally twice daily for 14 days followed by 14 days of rest plus sorafenib 400 mg administered orally twice daily for 28 days...
July 11, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29980894/a-phase-1-first-in-human-study-of-amg-900-an-orally-administered-pan-aurora-kinase-inhibitor-in-adult-patients-with-advanced-solid-tumors
#5
Michael Carducci, Montaser Shaheen, Ben Markman, Sara Hurvitz, Daruka Mahadevan, Dusan Kotasek, Oscar B Goodman, Erik Rasmussen, Vincent Chow, Gloria Juan, Gregory R Friberg, Erick Gamelin, Florian D Vogl, Jayesh Desai
Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases ( ClinicalTrials.gov : NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis...
July 7, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29971546/leptomeningeal-recurrence-after-long-term-alectinib-therapy-for-non-small-cell-lung-cancer-harboring-an-eml4-alk-fusion-protein
#6
Takahisa Kawamura, Haruyasu Murakami, Haruki Kobayashi, Kazuhisa Nakashima, Shota Omori, Kazushige Wakuda, Akira Ono, Hirotsugu Kenmotsu, Tateaki Naito, Masahiro Endo, Toshiaki Takahashi
The recent approval of anaplastic lymphoma kinase (ALK) inhibitors for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC) has dramatically transformed cancer therapy. However, leptomeningeal metastases (LM) are frequent and often devastating complications of ALK-rearranged NSCLC, and treatment against LM remains challenging. Herein we report a case of a 19-year-old male diagnosed with ALK-rearranged NSCLC with LM. He experienced heavy treatment before introduction of alectinib therapy, which continued for approximately 5...
July 3, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29956056/oral-metronomic-vinorelbine-omv-in-elderly-or-pretreated-patients-with-advanced-non-small-cell-lung-cancer-outcome-and-pharmacokinetics-in-the-real-world
#7
Felice Pasini, Carmen Barile, Donatella Caruso, Yasmina Modena, Anna Paola Fraccon, Laura Bertolaso, Daniela Menon, Francesca La Russa, Giorgio Crepaldi, Antonio Bononi, Roberto Spezzano, Roberto Padrini, Giuseppe Corona, Milena Gusella
Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients...
June 28, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29956055/cabozantinib-induced-serum-creatine-kinase-elevation-and-musculoskeletal-complaints
#8
Sarah E Stump, Young E Whang, Daniel J Crona
Cabozantinib is a multikinase inhibitor approved for the treatment of metastatic medullary thyroid cancer and advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy. While associations between serum creatine kinase (CK) elevations and other tyrosine kinase inhibitors used for the treatment of solid malignancies have been previously reported, we report a case of cabozantinib-associated CK elevation that was associated with musculoskeletal complaints by an RCC patient...
June 28, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29947013/inhibition-of-shp2-by-new-compounds-induces-differential-effects-on-ras-raf-erk-and-pi3k-akt-pathways-in-different-cancer-cell-types
#9
Cijo George Vazhappilly, Ekram Saleh, Wafaa Ramadan, Varsha Menon, Aya Mudhafar Al-Azawi, Hamadeh Tarazi, Hajjaj Abdu-Allah, Abdel-Nasser El-Shorbagi, Raafat El-Awady
Kinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate-4-thiazolinones in human cervical (HeLa) and breast (MCF-7 & MDA-MB-231) cancer cells. In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the allosteric site of SHP2...
June 27, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29947012/proliferative-cd8-pd-1-t-cell-infiltration-in-a-pembrolizumab-induced-cutaneous-adverse-reaction
#10
Kei Kunimasa, Taiki Isei, Harumi Nakamura, Madoka Kimura, Takako Inoue, Motohiro Tamiya, Kazumi Nishino, Toru Kumagai, Shin-Ichi Nakatsuka, Hiroko Endo, Masahiro Inoue, Fumio Imamura
Pembrolizumab, a humanized monoclonal immunoglobulin (Ig) G4 antibody that is directed against the human cell surface receptor PD-1, is a PD-1 pathway inhibitor that has been approved to treat various malignant diseases, including advanced non-small cell lung cancer (NSCLC). PD-1 is the major inhibitory receptor regulating T-cell exhaustion, and T-cells with high PD-1 expression lose their ability to eliminate cancer. PD-1 pathway blockade by pembrolizumab reinvigorates exhausted T-cells and restores their antitumor immune responses...
June 26, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29931585/euphol-a-tetracyclic-triterpene-from-euphorbia-tirucalli-induces-autophagy-and-sensitizes-temozolomide-cytotoxicity-on-glioblastoma-cells
#11
Viviane A O Silva, Marcela N Rosa, Vera Miranda-Gonçalves, Angela M Costa, Aline Tansini, Adriane F Evangelista, Olga Martinho, Adriana C Carloni, Chris Jones, João Paulo Lima, Luiz F Pianowski, Rui Manuel Reis
Glioblastoma (GBM) is the most frequent and aggressive type of brain tumor. There are limited therapeutic options for GBM so that new and effective agents are urgently needed. Euphol is a tetracyclic triterpene alcohol, and it is the main constituent of the sap of the medicinal plant Euphorbia tirucalli. We previously identified anti-cancer activity in euphol based on the cytotoxicity screening of 73 human cancer cells. We now expand the toxicological screening of the inhibitory effect and bioactivity of euphol using two additional glioma primary cultures...
June 22, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29931584/alteration-of-benzo-a-pyrene-biotransformation-by-resveratrol-in-apc-min-mouse-model-of-colon-carcinogenesis
#12
Ashley C Huderson, P V Rekha Devi, Mohammad S Niaz, Samuel E Adunyah, Aramandla Ramesh
Epidemiological surveys have revealed that environmental and dietary factors contribute to most of the human cancers. Our earlier studies have shown that resveratrol (RVT), a phytochemical reduced the tumor number, size and incidence of dysplasias induced by benzo(a)pyrene (BaP), an environmental toxicant in the Apc Min/+ mouse model of colon cancer. In this study we investigated to ascertain whether the preventive effects of RVT on BaP-induced colon carcinogenesis is a result of altered BaP biotransformation by RVT...
June 22, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29931583/dual-targeting-of-bromodomain-containing-4-by-azd5153-and-bcl2-by-azd4320-against-b-cell-lymphomas-concomitantly-overexpressing-c-myc-and-bcl2
#13
Tomoko Takimoto-Shimomura, Taku Tsukamoto, Saori Maegawa, Yuto Fujibayashi, Yayoi Matsumura-Kimoto, Yoshimi Mizuno, Yoshiaki Chinen, Yuji Shimura, Shinsuke Mizutani, Shigeo Horiike, Masafumi Taniwaki, Tsutomu Kobayashi, Junya Kuroda
Despite the recent therapeutic progress, the prognoses of diffuse large B-cell lymphomas (DLBCLs) that concomitantly overexpress c-MYC and BCL2, i.e., double hit lymphoma (DHL) and double expressing lymphoma (DEL), remain poor. This study examined triple targeting of c-MYC, BCL2 and the B-cell receptor (BCR) signaling pathway for DHL and DEL. We first used AZD5153, a novel bivalent inhibitor for bromodomain-containing 4 (BRD4), in DHL- and DEL-derived cell lines, because BRD4 regulates disease type-oriented key molecules for oncogenesis...
June 21, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29948359/methionine-gamma-lyase-from-clostridium-sporogenes-increases-the-anticancer-effect-of-doxorubicin-in-a549-cells-and-human-cancer-xenografts
#14
V S Pokrovsky, N Yu Anisimova, D Zh Davydov, S V Bazhenov, N V Bulushova, G B Zavilgelsky, V Y Kotova, I V Manukhov
The anti-cancer efficacy of methionine γ-lyase (MGL) from Clostridium sporogenes (C. sporogenes) is described. MGL was active against cancer models in vitro and in vivo. The calculated EC50 values for MGL were 4.4 U/ml for A549, 7.5 U/ml for SK-BR3, 2.4 U/ml for SKOV3, and 0.4 U/ml for MCF7 cells. The combination of doxorubicin (DOX) and MGL was more effective for A549 human lung cancer growth inhibition than either agent alone in vitro and in vivo. MGL reduced the EC50 of doxorubicin from 35.9 μg/mL to 0...
June 15, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29948358/survival-and-tolerance-to-sorafenib-in-child-pugh-b-patients-with-hepatocellular-carcinoma-a-prospective-study
#15
Cassia Regina Guedes Leal, Cristiane Magalhães, Daniel Barbosa, Diogo Aquino, Bernardo Carvalho, Elizabeth Balbi, Lucio Pacheco, Renata Perez, Paulo de Tarso Pinto, Sérgio Setubal
Sorafenib has been widely used to treat unresectable hepatocellular carcinoma (HCC) but most studies have been done in Child-Pugh A (CP-A) patients with well-preserved liver function. We evaluated the overall survival (OS) and tolerance to sorafenib in a large cohort of Child-Pugh B (CP-B) HCC patients as compared to CP-A HCC patients. We prospectively studied 130 patients with advanced HCC who started sorafenib between January 2011 and December 2015. Patients were classified as CP-A (n = 65) or CP-B (n = 65)...
June 13, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29948357/phase-ii-study-of-dfp-10917-a-deoxycytidine-analog-given-by-14-day-continuous-intravenous-infusion-for-chemotherapy-refractory-advanced-colorectal-cancer
#16
Amir Mehrvarz Sarshekeh, Henry Q Xiong, Kenzo Iizuka, Howard S Hochster, Scott Kopetz
Background DFP-10917 is a cytotoxic deoxycytidine analogue that causes DNA fragmentation, G2 /M-phase arrest, and apoptosis. This agent has been shown to have antitumor activity against colorectal cancer (CRC) in preclinical studies and to be tolerable in patients. The purpose of our phase II trial was to evaluate the safety, efficacy and pharmacogenomics of DFP-10917 as well as DNA damage studies in patients with advanced CRC refractory to cytotoxic chemotherapy. Methods In this single-arm, Simon two-stage, phase II trial, patients with chemotherapy-refractory advanced CRC received 2...
June 13, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29948356/a-phase-ib-study-of-sonidegib-lde225-an-oral-small-molecule-inhibitor-of-smoothened-or-hedgehog-pathway-in-combination-with-docetaxel-in-triple-negative-advanced-breast-cancer-patients-geicam-2012-12-edaline-study
#17
Manuel Ruiz-Borrego, Begoña Jimenez, Silvia Antolín, Jose A García-Saenz, Jesús Corral, Yolanda Jerez, José Trigo, Ander Urruticoechea, Helena Colom, Nuria Gonzalo, Carmen Muñoz, Sara Benito, Rosalía Caballero, Susana Bezares, Eva Carrasco, Federico Rojo, Miguel Martín
Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m2 ) in advanced TNBC patients. The primary objective was to ascertain the combination's maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles...
June 9, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29872938/the-poly-adp-ribose-polymerase-inhibitor-rucaparib-suppresses-proliferation-and-serves-as-an-effective-radiosensitizer-in-cervical-cancer
#18
Mei Tang, Qiuli Liu, Leyuan Zhou, Ling Chen, Xueqing Yang, Jinjin Yu, Yuan Wang, Haifeng Qiu
Objectives Our goal was to investigate the effects of rucaparib on the proliferation of cervical cancer cells and sensitivity to radiotherapy. Methods We used the human cervical cancer cell lines Hela and Siha and evaluated their viability and activity using various methods. Cellular proliferation was assessed by CCK-8 and clonogenic assays after treatment with rucaparib. Cell cycle analysis was performed using propidium iodide staining. Western immunoblotting analysis was used to detect the expression of cyclin D1 and CDK4...
June 6, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29860604/preclinical-study-of-the-antitumor-effect-of-sphingosine-1-phosphate-receptor-1-antibody-s1pr-1-antibody-against-human-breast-cancer-cells
#19
Shujun Xiao, Jian Yang
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite, which regulates a broad range of physiological and pathophysiological processes. The signaling of S1P via its cell surface receptor S1PR1 has been identified to play an important role in carcinogenesis, cancer growth and survival, and tumor metastasis. In this study, we evaluated whether a monoclonal antibody against S1PR1 (S1PR1 -antibody) could impose any effect on cell growth of human breast cancer SK-BR-3 and MDA-MB-231 cells. The S1PR1 -antibody exhibited cytostatic effect against both cell lines at the concentration of 4000 ng/mL...
June 2, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29855824/glp-overexpression-is-associated-with-poor-prognosis-in-chronic-lymphocytic-leukemia-and-its-inhibition-induces-leukemic-cell-death
#20
Juliana Carvalho Alves-Silva, Juliana Lott de Carvalho, Doralina Amaral Rabello, Teresa Raquel Tavares Serejo, Eduardo Magalhaes Rego, Francisco Assis Rocha Neves, Antonio Roberto Lucena-Araujo, Fábio Pittella-Silva, Felipe Saldanha-Araujo
Background Heterodimeric methyltransferases GLP (EHMT1/KMT1D) and G9a (EHMT2/KMT1C) are two closely related enzymes that promote the monomethylation and dimethylation of histone H3 lysine 9. Dysregulation of their activity has been implicated in several types of human cancer. Patients and methods Here, in order to investigate whether GLP/G9a exerts any impact on Chronic Lymphocytic Leukemia (CLL), GLP/G9a expression levels were assessed in a cohort of 50 patients and the effects of their inhibition were verified for the viability of CLL cells...
May 31, 2018: Investigational New Drugs
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