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Investigational New Drugs

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https://www.readbyqxmd.com/read/27909934/current-achievements-and-future-perspectives-of-metronomic-chemotherapy
#1
REVIEW
Adriana Romiti, Rosa Falcone, Michela Roberto, Paolo Marchetti
In recent years, many anticancer drugs have been tested at metronomic dosages for a variety of tumours. Mechanisms of action attributed to metronomic chemotherapy (MCT) include antiangiogenesis, immunomodulation, direct inhibition of tumour growth, effect on tumour initiating cells and the modulation of clonal evolution. An active clinical research, aimed at testing MCT in several cancers, has been conducted over the past 15 years. However, because the majority of available results come from earlier phase II studies, mainly performed in the area of breast cancer (BC), it is clear that there are areas still to be investigated...
December 1, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27900530/erratum-to-the-dna-methyltransferase-inhibitor-zebularine-exerts-antitumor-effects-and-reveals-batf2-as-a-poor-prognostic-marker-for-childhood-medulloblastoma
#2
Augusto Faria Andrade, Kleiton Silva Borges, Veridiana Kiill Suazo, Lenisa Geron, Carolina Alves Pereira Corrêa, Angel Mauricio Castro-Gamero, Elton José Rosas de Vasconcelos, Ricardo Santos de Oliveira, Luciano Neder, José Andres Yunes, Simone Dos Santos Aguiar, Carlos Alberto Scrideli, Luiz Gonzaga Tone
No abstract text is available yet for this article.
November 29, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27873130/phase-i-clinical-and-pharmacokinetic-study-of-pm01183-a-tetrahydroisoquinoline-lurbinectedin-in-combination-with-gemcitabine-in-patients-with-advanced-solid-tumors
#3
Luis Paz-Ares, Martin Forster, Valentina Boni, Sergio Szyldergemajn, Jesús Corral, Samantha Turnbull, Antonio Cubillo, Carlos Fernandez Teruel, Iker López Calderero, Mariano Siguero, Patrick Bohan, Emiliano Calvo
Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m(2) was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3...
November 21, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27853997/a-phase-i-trial-investigating-pulsatile-erlotinib-in-combination-with-gemcitabine-and-oxaliplatin-in-advanced-biliary-tract-cancers
#4
Laura W Goff, Dana B Cardin, Jennifer G Whisenant, Liping Du, Tatsuki Koyama, Kimberly B Dahlman, Safia N Salaria, Ruth T Young, Kristen K Ciombor, Jill Gilbert, Stephen James Smith, Emily Chan, Jordan Berlin
Advanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy. The purpose of this study was to assess the safety of pulsatile erlotinib with GEMOX...
November 16, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27853996/a-phase-1-study-combining-the-her3-antibody-seribantumab-mm-121-and-cetuximab-with-and-without-irinotecan
#5
James M Cleary, Autumn J McRee, Geoffrey I Shapiro, Sara M Tolaney, Bert H O'Neil, Jeffrey D Kearns, Sara Mathews, Rachel Nering, Gavin MacBeath, Akos Czibere, Sunil Sharma, W Michael Korn
Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFR-directed therapies. Methods This Phase 1 trial assessed the tolerability, maximum tolerated dose (MTD) and pharmacokinetic (PK) properties of the HER-3 antibody seribantumab in combination with cetuximab (Part I) or cetuximab and irinotecan (Part II) in patients with EGFR-dependent cancers. In Part I, escalating doses of seribantumab and cetuximab were administered. In Part II of the trial, escalating doses of seribantumab/cetuximab were combined with irinotecan 180 mg/m2 administered every two weeks...
November 16, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27838867/safety-of-raltegravir-based-antiretroviral-therapy-in-hiv-infected-patients-receiving-multi-kinase-inhibitors
#6
Pierre Loulergue, Mansouria Merad, Romain Coriat, Michel Ducreux, David Planchard, Valérie Boige, Axel Le Cesne, Thomas M Gregory, Vianney Poinsignon, Angelo Paci, Olivier Mir
Background The risk of pharmacokinetic interaction is important in HIV-infected cancer patients receiving concomitantly highly active antiretroviral therapy (HAART) and anti-cancer systemic treatments. We aimed to evaluate the safety profile of raltegravir-based HAART in cancer patients receiving multi-kinase inhibitors (MKIs). Patients and Methods We conducted a retrospective medical record review of adult, HIV-infected cancer patients treated in our institutions from January 2010 to December 2015. Patients eligible for the present analysis were those receiving a raltegravir-based HAART at the time of the initiation of a MKI for the treatment of advanced solid tumors...
November 12, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27826831/phase-1b-study-of-orteronel-in-postmenopausal-women-with-hormone-receptor-positive-hr-metastatic-breast-cancer
#7
Murtuza Rampurwala, Kari B Wisinski, Mark E Burkard, Sima Ehsani, Ruth M O'Regan, Lakeesha Carmichael, KyungMann Kim, Jill Kolesar, Amye J Tevaarwerk
Introduction Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of orteronel in women; escalation was via standard 3 + 3 design...
November 8, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27812884/alofanib-an-allosteric-fgfr2-inhibitor-has-potent-effects-on-ovarian-cancer-growth-in-preclinical-studies
#8
Alexandra Tyulyandina, Daniel Harrison, Wei Yin, Evgenia Stepanova, Dmitry Kochenkov, Eliso Solomko, Nina Peretolchina, Frits Daeyaert, Jean-Baptiste Joos, Koen Van Aken, Mikhail Byakhov, Evgenia Gavrilova, Sergei Tjulandin, Ilya Tsimafeyeu
Purpose Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. We investigated antitumor activity of alofanib (RPT835), a novel allosteric FGFR2 inhibitor, in ovarian cancer in vitro and in vivo. Methods Equal amounts of ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1-3 protein expression using Wes. To assess the efficacy of alofanib on FGF-mediated cell proliferation, SKOV3 cells were incubated and were treated with serially diluted alofanib...
November 3, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27796680/erlotinib-pharmacokinetics-a-critical-parameter-influencing-acute-toxicity-in-elderly-patients-over-75%C3%A2-years-old
#9
Frederic Bigot, Pascaline Boudou-Rouquette, Jennifer Arrondeau, Audrey Thomas-Schoemann, Camille Tlemsani, Jeanne Chapron, Olivier Huillard, Anatole Cessot, Michel Vidal, Jerome Alexandre, Benoit Blanchet, Francois Goldwasser
Background Older non-small cell lung cancer (NSCLC) patients under erlotinib are reported to experience more acute toxicity. We hypothesized that modifications in erlotinib pharmacokinetics might explain this observation. Methods A monocentric prospective clinico-pharmacological study included stage IIIb/IV NSCLC consecutive pts. treated with erlotinib. The plasma concentration of erlotinib (Ce) was measured at steady state on day 15. We studied the relationship between age > 75 years, and Ce, using the Mann-Whitney U test and with the occurrence of acute toxicity, using a Fisher's test...
October 29, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27785591/the-dna-methyltransferase-inhibitor-zebularine-exerts-antitumor-effects-and-reveals-batf2-as-a-poor-prognostic-marker-for-childhood-medulloblastoma
#10
Augusto Faria Andrade, Kleiton Silva Borges, Veridiana Kiill Suazo, Lenisa Geron, Carolina Alves Pereira Corrêa, Angel Mauricio Castro-Gamero, Elton José Rosas de Vasconcelos, Ricardo Santos de Oliveira, Luciano Neder, José Andres Yunes, Simone Dos Santos Aguiar, Carlos Alberto Scrideli, Luiz Gonzaga Tone
Medulloblastoma (MB) is the most common solid tumor among pediatric patients and corresponds to 20 % of all pediatric intracranial tumors in this age group. Its treatment currently involves significant side effects. Epigenetic changes such as DNA methylation may contribute to its development and progression. DNA methyltransferase (DNMT) inhibitors have shown promising anticancer effects. The agent Zebularine acts as an inhibitor of DNA methylation and shows low toxicity and high efficacy, being a promising adjuvant agent for anti-cancer chemotherapy...
October 26, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27783256/predictive-factors-of-renal-toxicities-related-to-anti-vegfr-multikinase-inhibitors-in-phase-1-trials
#11
Emilie Boissier, Olivier Mir, Antoine Hollebecque, Hassan Izzedine, Stéphane Ederhy, Anas Gazzah, Rastislav Bahleda, Christophe Massard, Isabelle Macquin-Mavier, Christophe Tournigand, Jean-Philippe Spano, Jean-Charles Soria, Benoît Rousseau
Purpose Renal toxicities are common with angiogenesis multikinase inhibitors (AMKI), and can be limiting in phase I trials. Factors associated with such toxicities are poorly known. The aims of this exploratory study were to describe renovascular toxicities associated with AMKI, impact on drug development and to identify baseline parameters associated with the occurrence of renal toxicities in phase I trials. Methods Consecutive patients treated with AMKI in Gustave Roussy phase I unit between October 2005 and August 2013 were included...
October 25, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27783255/targeting-the-protein-ubiquitination-machinery-in-melanoma-by-the-nedd8-activating-enzyme-inhibitor-pevonedistat-mln4924
#12
Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27726093/a-photodynamic-bifunctional-conjugate-for-prostate-cancer-an-in-vitro-mechanistic-study
#13
Valentina Rapozzi, Greta Varchi, Emilia Della Pietra, Claudia Ferroni, Luigi E Xodo
Photodynamic therapy (PDT) has drawn considerable attention for its efficacy against certain types of cancers. It shows however limits in the case of deep cancers, favoring tumor recurrence under suboptimal conditions. More insight into the molecular mechanisms of PDT-induced cytotoxicity and cytoprotection is essential to extend and strengthen this therapeutic modality. As PDT induces iNOS/NO in both tumor and microenvironment, we examined the role of nitric oxide (NO) in cytotoxicity and cytoprotection. Our findings show that NO mediates its cellular effects by acting on the NF-κB/YY1/RKIP loop, which controls cell growth and apoptosis...
October 11, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27718039/4-methylumbelliferone-and-imatinib-combination-enhances-senescence-induction-in-chronic-myeloid-leukemia-cell-lines
#14
Silvina Laura Lompardía, Mariángeles Díaz, Daniela Laura Papademetrio, Matías Pibuel, Élida Álvarez, Silvia Elvira Hajos
Chronic myeloid leukemia (CML) is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome which encodes a constitutively activated tyrosine kinase (BCR-ABL). The first line treatment for CML consists on BCR-ABL inhibitors such as Imatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, it is of great value to find molecules that enhance the anti-proliferative effect of first-line drugs. Hyaluronan is the main glycosaminglican of the extracellular matrix which is involved in tumor progression and multidrug resistance...
October 8, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27718038/evaluating-the-role-of-phase-i-expansion-cohorts-in-oncologic-drug-development
#15
Robin E Norris, Mohadese Behtaj, Pingfu Fu, Afshin Dowlati
Importance Use of expansion cohorts (EC) in phase I trials is increasing. However, the utility of phase I EC in aiding drug development is unclear. We sought to determine factors associated with the inclusion of EC in phase I studies and the impact of EC on subsequent clinical development. Methods We performed a systematic review of all phase I trials published in the Journal of Clinical Oncology between June 2004 and May 2014. Presence of an EC, number of participants, funding source, class of agent, tumor type, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) were identified...
October 7, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27687047/incidence-of-infusion-reactions-to-anti-neoplastic-agents-in-early-phase-clinical-trials-the-md-anderson-cancer-center-experience
#16
Manojkumar Bupathi, Joud Hajjar, Stacie Bean, Siqing Fu, David Hong, Daniel Karp, Bettzy Stephen, Kenneth Hess, Funda Meric-Bernstam, Aung Naing
Infusion reactions (IRs) to anti-neoplastic agents require prompt recognition and immediate treatment to avert significant complications. We conducted a retrospective review of the medical records of consecutive patients who received anti-neoplastic therapy in the outpatient treatment center of the Department of Investigational Cancer Therapeutics from January 1, 2013 to November 30, 2013. Of the 597 patients who received treatment, 9 (1.5 %) had IRs (all ≤ grade 2). The most common IRs observed on first occurrence were chills (n = 5), itching, rash, and facial flushing (n = 3 each)...
September 29, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27655216/propolis-extracts-from-the-northern-region-of-thailand-suppress-cancer-cell-growth-through-induction-of-apoptosis-pathways
#17
Supakit Khacha-Ananda, Khajornsak Tragoolpua, Panuwan Chantawannakul, Yingmanee Tragoolpua
The continual increase in mortality rates and number of cancer cases is a matter of serious concern in developing countries. The incorporation of natural products into classical cancer treatment approaches is a promising direction. The mechanisms of A549 and HeLa cancer cell death induction by ethanolic extracts of propolis samples from Phayao, Chiang Mai, and Nan provinces in northern Thailand were investigated in this study. The propolis extract from Chiang Mai showed the highest antioxidant activity and the greatest total phenolic content...
September 21, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27650277/a-phase-i-dose-escalation-study-of-tak-733-an-investigational-oral-mek-inhibitor-in-patients-with-advanced-solid-tumors
#18
Alex A Adjei, Patricia LoRusso, Antoni Ribas, Jeffrey A Sosman, Anna Pavlick, Grace K Dy, Xiaofei Zhou, Esha Gangolli, Michelle Kneissl, Stephanie Faucette, Rachel Neuwirth, Viviana Bózon
Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1...
September 21, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27644694/new-water-soluble-palladium-ii-complexes-of-lidocaine-and-phenylcyanamide-derivative-ligands-cytotoxicity-and-cellular-response-mechanisms
#19
Leila Tabrizi, Hossein Chiniforoshan
Three new palladium(II) complexes of lidocaine and phenylcyanamide derivative ligands of formula K[Pd(2,6-Me2pcyd)2(LC)], 1, K[Pd(2,6-Et2pcyd)2(LC)], 2, K[Pd(2,6-Cl2pcyd)2(LC)], 3 (LC: lidocaine, 2,6-Me2pcyd: 2,6-dimethyl phenylcyanamide, 2,6-Et2pcyd: 2,6-diethyl phenylcyanamide, 2,6-Cl2pcyd: 2,6-dichloro phenylcyanamide) have been synthesized and fully characterized. The complexes 1-3 revealed a significant in vitro antiproliferative activity against human ovarian carcinoma (A2780), colorectal adenocarcinoma (HT29), breast (MCF-7), liver hepatocellular carcinoma (HepG-2) and lung adenocarcinoma (A549) cancer cell lines...
September 19, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27604635/a-retrospective-analysis-of-14-consecutive-chinese-patients-with-unresectable-or-metastatic-alveolar-soft-part-sarcoma-treated-with-sunitinib
#20
Ting Li, Lei Wang, Huijie Wang, Shujuan Zhang, Atikan Kawuli, Xiaowei Zhang, Zhiguo Luo, Chunmeng Wang
Background The study was aim to assess the efficacy and safety of sunitinib on 14 Chinese patients with locally unresectable or metastatic Alveolar Soft Part Sarcoma (ASPS) at two institutions retrospectively. Methods Patients were treated with 37.5 mg of sunitinib once daily continuously without a scheduled off-treatment period. Dose holds or reductions were recommended for grade 3 AEs but were required for grade 4 AEs. Restarting treatment of sunitinib was allowed when AEs returned back to grade 1 or disappeared...
September 8, 2016: Investigational New Drugs
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