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Investigational New Drugs

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https://www.readbyqxmd.com/read/29333575/a-phase-1-dose-escalation-study-of-pf-06664178-an-anti-trop-2-aur0101-antibody-drug-conjugate-in-patients-with-advanced-or-metastatic-solid-tumors
#1
Gentry T King, Keith D Eaton, Brandon R Beagle, Christopher J Zopf, Gilbert Y Wong, Heike I Krupka, Steven Y Hua, Wells A Messersmith, Anthony B El-Khoueiry
Purpose and Methods Trop-2 is a glycoprotein over-expressed in many solid tumors but at low levels in normal human tissue, providing a potential therapeutic target. We conducted a phase 1 dose-finding study of PF-06664178, an antibody-drug conjugate that targets Trop-2 for the selective delivery of the cytotoxic payload Aur0101. The primary objective was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included further characterization of the safety profile, pharmacokinetics and antitumor activity...
January 15, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29313280/the-in-vitro-assessment-of-dipyridophenazine-complexes-in-h-ras-oncogene-transformed-rat-embryo-fibroblast-5rp7-cell-line
#2
Ayse Kaplan, Kadriye Benkli, Ayse Tansu Koparal
Purpose The aim of this study is to detect apoptotic and cytotoxic/antiproliferative effects of a ligand substance and its metal derivatives. The substances were investigated by using an h-ras oncogene transformed rat embryo fibroblast cell line (5RP7). Methods The cytotoxic influences of dipyrido[3,2-a:2',3'c]phenazine ligand, dipyrido[3,2-a:2',3'c] phenazine-platinum(II) complex ([Pt(dppz)Cl2]) and dipyrido[3,2-a:2',3'c] phenazine-gold(III) complex ([Au(dppz)Cl2]Cl) were determined with MTT (3[4,5-dimetiltiyazol2-yl]-2,5-difeniltetrazolyum bromid) assay on 5RP7 cells...
January 8, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29313279/a-phase-1-study-of-parp-inhibitor-abt-767-in-advanced-solid-tumors-with-brca1-2-mutations-and-high-grade-serous-ovarian-fallopian-tube-or-primary-peritoneal-cancer
#3
Diane A J van der Biessen, Jourik A Gietema, Maja J A de Jonge, Ingrid M E Desar, Martha W den Hollander, Matthew Dudley, Martin Dunbar, Robert Hetman, Camille Serpenti, Hao Xiong, Rajendar K Mittapalli, Kirsten M Timms, Peter Ansell, Christine K Ratajczak, Stacie Peacock Shepherd, Carla M L van Herpen
Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined...
January 8, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29297149/repurposing-of-the-cdk-inhibitor-pha-767491-as-a-nrf2-inhibitor-drug-candidate-for-cancer-therapy-via-redox-modulation
#4
Hsiu-Yu Liu, Andrea Z Tuckett, Myles Fennell, Ralph Garippa, Johannes L Zakrzewski
Oxidative stress and cellular response mechanisms such as NRF2-mediated antioxidant responses play differential roles in healthy and diseased cells. Constant generation and elimination of high levels of reactive oxygen species is a hallmark of many cancer cell types; this phenomenon is not observed during steady state of healthy cells. Manipulation of NRF2 transcriptional activity and the cellular redox homeostasis therefore has potential to be therapeutically exploitable for cancer therapy by preferentially targeting cancer cells for induction of oxidative stress...
January 3, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29277856/a-phase-iia-study-of-ha-irinotecan-formulation-of-hyaluronic-acid-and-irinotecan-targeting-cd44-in-extensive-stage-small-cell-lung-cancer
#5
Muhammad Alamgeer, D Neil Watkins, Ilia Banakh, Beena Kumar, Daniel J Gough, Ben Markman, Vinod Ganju
Preclinical studies in small cell lung cancer (SCLC) have shown that hyaluronic acid (HA) can be effectively used to deliver chemotherapy and selectively decrease CD44 expressing (stem cell-like) tumour cells. The current study aimed to replicate these findings and obtain data on safety and activity of HA-irinotecan (HA-IR). Eligible patients with extensive stage SCLC were consented. A safety cohort (n = 5) was treated with HA-IR and Carboplatin (C). Subsequently, the patients were randomised 1:1 to receive experimental (HA-IR + C) or standard (IR + C) treatment, to a maximum of 6 cycles...
December 26, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29273857/development-of-a-dietary-formulation-of-the-sheta2-chemoprevention-drug-for-mice
#6
Doris M Benbrook, Naveena B Janakiram, Vishal Chandra, Gopal Pathuri, Venkateshwar Madka, Nicole C Stratton, Chioniso P Masamha, Cassadie N Farnsworth, Lucila Garcia-Contreras, Manolya Kukut Hatipoglu, Stan Lighfoot, Chinthalapally V Rao
Development of cancer chemoprevention compounds requires enhanced consideration for toxicity and route of administration because the target population is healthy. The small molecule drug, SHetA2 (NSC 726189), exhibited in vivo chemoprevention activity and lack of toxicity when administered by oral gavage. Our objective was to determine if a dietary formulation of SHetA2 could achieve effective tissue drug levels without toxicity. C57bl/6 J mice were monitored on modified American Institute of Nutrition (AIN)76A diet mixed with SHetA2 in a 3:1 ratio with Kolliphor HS15, a self-emulsifying drug delivery system (SEDDS) to deliver 37...
December 22, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29250742/a-randomized-phase-2-study-of-a-hsp27-targeting-antisense-apatorsen-with-prednisone-versus-prednisone-alone-in-patients-with-metastatic-castration-resistant-prostate-cancer
#7
Evan Y Yu, Susan L Ellard, Sebastien J Hotte, Joel R Gingerich, Anthony M Joshua, Martin E Gleave, Kim N Chi
Purpose Heat shock protein 27 (Hsp27) is implicated in prostate cancer progression. Apatorsen is a second generation phosphorothioate antisense inhibitor of Hsp27 expression. We evaluated apatorsen in patients with metastatic castration resistant prostate cancer (mCRPC). Experimental design Eligible patients were randomized 1:1 to receive intravenous apatorsen (3 loading doses of 600 mg within 5-9 days followed by weekly doses of 1000 mg) with oral prednisone 5 mg twice daily or prednisone alone. The primary endpoint was disease progression at 12 weeks...
December 18, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29250741/everolimus-induced-mood-changes-in-breast-cancer-patients-a-case-control-study
#8
Olivier Mir, Alexandre Salvador, Sarah Dauchy, Stanislas Ropert, Cédric Lemogne, Raphaël Gaillard
Introduction The PI3K/Akt/mTOR pathway plays a critical role in cancer cell growth, proliferation and angiogenesis, but also in brain homeostasis and the pathophysiology of mood disorders. The impact of the mTOR inhibitor everolimus on the mood of breast cancer patients is unknown. Materials and methods Consecutive, post-menopausal metastatic breast cancer patients receiving hormone therapy +/- everolimus were prospectively followed-up using the Beck Depression Inventory (BDI) and the MADRS (Montgomery and Asberg Depression Rating Scale) questionnaires...
December 18, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29234946/comparison-of-published-and-unpublished-phase-i-clinical-cancer-trials-an-analysis-of-the-clinicltrials-gov-database
#9
REVIEW
D Shepshelovich, H Goldvaser, L Wang, A R Abdul Razak
Introduction The role of phase I cancer trials is constantly evolving and they are increasingly being used in 'go/no' decisions in drug development. As a result, there is a growing need to ensure trials are published when completed. There are limited data on the publication rate and the factors associated with publication in phase I trials. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching publications published prior to April 1, 2017...
December 13, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29196957/phase-1-and-pharmacokinetic-study-of-ly3007113-a-p38-mapk-inhibitor-in-patients-with-advanced-cancer
#10
Jonathan W Goldman, Lee S Rosen, Anthony W Tolcher, Kyriakos Papadopoulos, Muralidhar Beeram, Peipei Shi, Celine Pitou, Robert Bell, Palaniappan Kulanthaivel, Xuekui Zhang, Aaron Fink, Edward M Chan, Ashwin Shahir, Daphne Farrington, Amita Patnaik
Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalation), LY3007113 was administered orally every 12 h (Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-day cycle until the maximum tolerated dose (MTD) was reached...
December 1, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29192354/prognostic-implication-of-inflammation-based-prognostic-scores-in-patients-with-intrahepatic-cholangiocarcinoma-treated-with-first-line-gemcitabine-plus-cisplatin
#11
Hyungwoo Cho, Changhoon Yoo, Kyu-Pyo Kim, Jae Ho Jeong, Jihoon Kang, Heung-Moon Chang, Sang Soo Lee, Do Hyun Park, Tae Jun Song, Sung Koo Lee, Myung-Hwan Kim, Han Chu Lee, Young-Suk Lim, Kang Mo Kim, Ju Hyun Shim, Shin Hwang, Gi-Won Song, Deok-Bog Moon, Jae Hoon Lee, Young-Joo Lee, Baek-Yeol Ryoo
Background We aimed to comprehensively evaluate the prognostic value of inflammation-based prognostic scores, including the modified Glasgow Prognostic Score (mGPS), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR), exclusively in patients with advanced intrahepatic cholangiocarcinoma (iCCA). Methods Between May 2010 and April 2015, 305 patients with histologically documented unresectable or metastatic iCCA were treated with first-line gemcitabine plus cisplatin (GemCis). Among these, 257 patients had complete data for inflammation-based prognostic scores and were included...
December 1, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29188469/met-targeting-antibody-emibetuzumab-and-kinase-inhibitor-merestinib-as-single-agent-or-in-combination-in-a-cancer-model-bearing-met-exon-14-skipping
#12
S Betty Yan, Suzane L Um, Victoria L Peek, Jennifer R Stephens, Wei Zeng, Bruce W Konicek, Ling Liu, Jason R Manro, Volker Wacheck, Richard A Walgren
Purpose Approximately 3% of lung cancer bears mutations leading to MET exon 14 skipping, an oncogenic driver which is further evidenced by case reports of patient response to MET kinase inhibitor treatment. Approximately 15% of tumors harboring MET exon14 skipping have concurrent MET amplification. Experimental Design Merestinib is a type II MET kinase inhibitor. Emibetuzumab, a bivalent anti-MET antibody, internalizes MET receptor. Each single agent and the combination were evaluated in the Hs746t gastric cancer line bearing MET exon14 skipping and MET amplification...
November 29, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29177975/hepatic-safety-analysis-of-trabectedin-results-of-a-pharmacokinetic-study-with-trabectedin-in-patients-with-hepatic-impairment-and-experience-from-a-phase-3-clinical-trial
#13
Emiliano Calvo, Analia Azaro, Jordi Rodon, Luc Dirix, Manon Huizing, Francis Mark Senecal, Patricia LoRusso, Lorrin Yee, Italo Poggesi, Jan de Jong, Spyros Triantos, Youn C Park, Roland E Knoblauch, Trilok V Parekh, George D Demetri, Margaret von Mehren
Purpose Trabectedin is metabolized by the liver and has been associated with transient, noncumulative transaminase elevation. Two recent studies further characterize hepatic tolerability with trabectedin therapy: a phase 1 pharmacokinetic study (Study #1004; NCT01273493) in patients with advanced malignancies and hepatic impairment (HI), and a phase 3 study (Study #3007; NCT01343277) of trabectedin vs. dacarbazine in patients with advanced sarcomas and normal hepatic function. Methods In Study #1004, patients received a single 3-h intravenous (IV) infusion of trabectedin: control group, trabectedin 1...
November 27, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29177974/antitumor-activity-of-raloxifene-targeted-poly-styrene-maleic-acid-poly-amide-ether-ester-imide-co-polymeric-nanomicelles-loaded-with-docetaxel-in-breast-cancer-bearing-mice
#14
Saeede Enteshari, Jaleh Varshosaz, Mohsen Minayian, Farshid Hassanzadeh
Purpose Raloxifene (RA) receptors have over-expressed GPER-positive breast cancer tumors. The purpose of this work was to evaluate the antitumor activity and pharmacokinetic behavior of docetaxel (DTX), loaded in RA-targeted nanomicelles, which were designed to overcome a lack of specific distribution and inadequate DTX concentration in tumor tissues, as well as its cytotoxicity and damage to normal tissues. Methods DTX-loaded RA-targeted poly(styrene maleic acid) (SMA)- poly(amide-ether-esterimide)-poly(ethylene glycol) (PAEEI-PEG) nanomicelles were prepared; then, their antitumor activity and survival rate were studied in MC4-L2 tumors induced in BALB/c mice...
November 27, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29170886/phase-ii-study-of-doxorubicin-and-thalidomide-in-patients-with-refractory-aggressive-fibromatosis
#15
Xin Liu, Huijie Wang, Xianghua Wu, Xiaonan Hong, Zhiguo Luo
Background To evaluate the efficacy and safety of doxorubicin (ADM) combined with thalidomide (THA) as a first-line treatment for patients with refractory aggressive fibromatosis (AF). Patients and Methods Eligible patients were treated with ADM 30 mg/m(2) on days 1-2 and THA 200 mg nightly on days 1-21 every 3 weeks for a maximum of six cycles. THA was then continued for a total of 1 year. The primary end point was response rate (RR). Results Fifteen patients were enrolled in the study. No patient had a complete response, but five patients had partial responses, resulting in a RR of 33%...
November 23, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29159766/incidence-of-immune-related-adverse-events-and-its-association-with-treatment-outcomes-the-md-anderson-cancer-center-experience
#16
Takeo Fujii, Rivka R Colen, Mehmet Asim Bilen, Kenneth R Hess, Joud Hajjar, Maria E Suarez-Almazor, Anas Alshawa, David S Hong, Apostolia Tsimberidou, Filip Janku, Jing Gong, Bettzy Stephen, Vivek Subbiah, Sarina A Piha-Paul, Siqing Fu, Padmanee Sharma, Tito Mendoza, Anisha Patel, Selvi Thirumurthi, Ajay Sheshadri, Funda Meric-Bernstam, Aung Naing
Background Immunotherapy is emerging as the cornerstone for treatment of patients with advanced cancer, but significant toxicity (immune-related adverse events [irAEs]) associated with unbridled T cell activity remains a concern. Patients and methods A retrospective review of the electronic medical records of 290 patients with advanced cancer treated on an immunotherapy-based clinical trial in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center between February 2010 and September 2015 was performed...
November 21, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29150734/the-sirtuin-1-2-inhibitor-tenovin-1-induces-a-nonlinear-apoptosis-inducing-factor-dependent-cell-death-in-a-p53-null-ewing-s-sarcoma-cell-line
#17
Christian Marx, Lisa Marx-Blümel, Nora Lindig, René Thierbach, Doerte Hoelzer, Sabine Becker, Susan Wittig, Roland Lehmann, Hortense Slevogt, Thorsten Heinzel, Zhao-Qi Wang, James F Beck, Jürgen Sonnemann
The sirtuin 1/2 inhibitor tenovin-1 activates p53 and may have potential in the management of cancer. Here, we investigated the responsiveness of Ewing's sarcoma cells to tenovin-1. We examined its effects in two Ewing's sarcoma cell lines with different p53 status, i.e. in p53 wild-type and p53 null cells. Effects were assessed by flow cytometric analyses of cell death, mitochondrial membrane depolarization and reactive oxygen species (ROS) generation, by caspase 3/7 activity measurement, by mRNA expression profiling and by immunoblotting...
November 18, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29147815/atp-binding-cassette-transporters-limit-the-brain-penetration-of-wee1-inhibitors
#18
Mark C de Gooijer, Levi C M Buil, Jos H Beijnen, Olaf van Tellingen
Introduction Wee1 is an important kinase involved in the G2 cell cycle checkpoint and frequently upregulated in intracranial neoplasms such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). Two small molecules are available that target Wee1, AZD1775 and PD0166285, and clinical trials with AZD1775 have already been started. Since GBM and DIPG are highly invasive brain tumors, they are at least to some extent protected by the blood-brain barrier (BBB) and its ATP-binding cassette (ABC) efflux transporters...
November 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29139009/lfm-a13-a-potent-inhibitor-of-polo-like-kinase-inhibits-breast-carcinogenesis-by-suppressing-proliferation-activity-and-inducing-apoptosis-in-breast-tumors-of-mice
#19
Kazim Sahin, Mehmet Tuzcu, Mehmet Yabas, Cemal Orhan, Nurhan Sahin, Ibrahim H Ozercan
The goals of the present study were to define the anticancer activity of LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)-propenamide), a potent inhibitor of Polo-like kinase (PLK), in a mouse mammary cancer model induced by 7,12-dimethylbenz(a)anthracene (DMBA) in vivo and explore its anticancer mechanism(s). We also examined whether the inhibition of PLK by LFM-A13 would improve the efficiency of paclitaxel in breast cancer growth in vivo. To do this, female BALB/c mice received 1 mg of DMBA once a week for 6 weeks with oral gavage...
November 15, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29134432/phase-iii-study-of-dulanermin-recombinant-human-tumor-necrosis-factor-related-apoptosis-inducing-ligand-apo2-ligand-combined-with-vinorelbine-and-cisplatin-in-patients-with-advanced-non-small-cell-lung-cancer
#20
Xuenong Ouyang, Meiqi Shi, Fangwei Jie, Yuxian Bai, Peng Shen, Zhuang Yu, Xiuwen Wang, Cheng Huang, Min Tao, Zhehai Wang, Conghua Xie, Qi Wu, Yongqian Shu, Baohui Han, Fengchun Zhang, Yiping Zhang, Chunhong Hu, Xitao Ma, Yongjie Liang, Anlan Wang, Bing Lu, Yi Shi, Jinfei Chen, Zhixiang Zhuang, Jiejun Wang, Jianjin Huang, Changhui Wang, Chunxue Bai, Xin Zhou, Qiang Li, Feng Chen, Hao Yu, Jifeng Feng
Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m(2) on days 1 and 8 and cisplatin 30 mg/m(2) on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent...
November 14, 2017: Investigational New Drugs
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