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Investigational New Drugs

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https://www.readbyqxmd.com/read/28204981/phase-1b-trial-of-proteasome-inhibitor-carfilzomib-with-irinotecan-in-lung-cancer-and-other-irinotecan-sensitive-malignancies-that-have-progressed-on-prior-therapy-onyx-ist-reference-number-car-ist-553
#1
Susanne M Arnold, Kari Chansky, Markos Leggas, Michael A Thompson, John L Villano, John Hamm, Rachel E Sanborn, Glen J Weiss, Gurkamal Chatta, Maria Q Baggstrom
Introduction Proteasome inhibition is an established therapy for many malignancies. Carfilzomib, a novel proteasome inhibitor, was combined with irinotecan to provide a synergistic approach in relapsed, irinotecan-sensitive cancers. Materials and Methods Patients with relapsed irinotecan-sensitive cancers received carfilzomib (Day 1, 2, 8, 9, 15, and 16) at three dose levels (20/27 mg/m2, 20/36 mg/m2 and 20/45 mg/m2/day) in combination with irinotecan (Days 1, 8 and 15) at 125 mg/m2/day. Key eligibility criteria included measurable disease, a Zubrod PS of 0 or 1, and acceptable organ function...
February 16, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28194539/phase-i-trial-of-mek-1-2-inhibitor-pimasertib-combined-with-mtor-inhibitor-temsirolimus-in-patients-with-advanced-solid-tumors
#2
Monica Mita, Siqing Fu, Sarina Anne Piha-Paul, Filip Janku, Alain Mita, Ronald Natale, Wei Guo, Charles Zhao, Razelle Kurzrock, Aung Naing
Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3 + 3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated...
February 13, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28188407/phase-ii-study-of-the-antibody-drug-conjugate-tak-264-mln0264-in-patients-with-metastatic-or-recurrent-adenocarcinoma-of-the-stomach-or-gastroesophageal-junction-expressing-guanylyl-cyclase-c
#3
Khaldoun Almhanna, Maria Luisa Limon Miron, David Wright, Antonio Cubillo Gracian, Richard A Hubner, Jean-Luc Van Laethem, Carolina Muriel López, Maria Alsina, Frederico Longo Muñoz, Johanna Bendell, Irfan Firdaus, Wells Messersmith, Zhan Ye, Adedigbo A Fasanmade, Hadi Danaee, Thea Kalebic
Background The first-in-class antibody-drug conjugate TAK-264 (formerly MLN0264) consists of an antibody targeting guanylyl cyclase C (GCC) conjugated to monomethyl auristatin E (MMAE) via a peptide linker. This phase II study evaluated the efficacy and safety of TAK-264 in patients with adenocarcinoma of the stomach or gastroesophageal junction expressing GCC, who had progressed on ≥1 line of prior therapy. Methods This study used a two-stage design, with an interim analysis conducted after stage I to determine whether to continue to stage II or discontinue on the grounds of futility...
February 11, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28185040/erratum-to-zebrafish-phenotypic-screen-identifies-novel-notch-antagonists
#4
Vithya Velaithan, Kazuhide Shaun Okuda, Mei Fong Ng, Norazwana Samat, Sze Wei Leong, Siti Munirah Mohd Faudzi, Faridah Abas, Khozirah Shaari, Sok Ching Cheong, Pei Jean Tan, Vyomesh Patel
No abstract text is available yet for this article.
February 10, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28164251/state-dependent-block-of-voltage-gated-sodium-channels-by-the-casein-kinase-1-inhibitor-ic261
#5
Karl J Föhr, Uwe Knippschild, Anna Herkommer, Michael Fauler, Christian Peifer, Michael Georgieff, Oliver Adolph
Background and Purpose IC261 (3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one) has previously been introduced as an isoform specific inhibitor of casein kinase 1 (CK1) causing cell cycle arrest or cell death of established tumor cell lines. However, it is reasonable to assume that not all antitumor activities of IC261 are mediated by the inhibition of CK1. Meanwhile there is growing evidence that functional voltage-gated sodium channels are also implicated in the progression of tumors as their blockage suppresses tumor migration and invasion of different tumor cell lines...
February 6, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28161886/phase-1-study-of-narnatumab-an-anti-ron-receptor-monoclonal-antibody-in-patients-with-advanced-solid-tumors
#6
Patricia M LoRusso, Mrinal Gounder, Shadia I Jalal, Valérie André, Siva Rama Prasad Kambhampati, Nick Loizos, Jennifer Hall, Timothy R Holzer, Aejaz Nasir, Jan Cosaert, John Kauh, E Gabriela Chiorean
Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles...
February 4, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28155045/association-of-an-aurora-kinase-a-aurka-gene-polymorphism-with-progression-free-survival-in-patients-with-advanced-urothelial-carcinoma-treated-with-the-selective-aurora-kinase-a-inhibitor-alisertib
#7
Andrea Necchi, Giulia Pintarelli, Daniele Raggi, Patrizia Giannatempo, Francesca Colombo
Background and purpose Salvage therapies for urothelial carcinoma are needed. A single-arm trial in patients with advanced or metastatic urothelial carcinoma refractive to other therapies found that alisertib, a selective inhibitor of aurora kinase A, maintained stable disease in a few cases, despite a low objective response rate. To better understand why some patients benefited from alisertib, we genotyped the 22 patients of this pilot trial for two single nucleotide polymorphisms (rs2273535 and rs1047972) in AURKA, the gene encoding aurora kinase A, and looked for associations with survival and treatment response...
February 3, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28150074/a-phase-ii-study-of-carboplatin-plus-weekly-paclitaxel-with-bevacizumab-for-elderly-patients-with-non-squamous-non-small-cell-lung-cancer-nej016
#8
Satoru Miura, Makoto Maemondo, Akira Iwashima, Toshiyuki Harada, Shunichi Sugawara, Kunihiko Kobayashi, Akira Inoue, Taku Nakagawa, Yuichi Takiguchi, Hiroshi Watanabe, Takashi Ishida, Masaki Terada, Hiroshi Kagamu, Akihiko Gemma, Hirohisa Yoshizawa
Background The efficacy and safety of bevacizumab in elderly patients with non-small cell lung cancer remain controversial. This study focused on both selecting fit elderly patients and overcoming interpatient variability with respect to pharmacodynamics. Methods Elderly (age: ≥70 years) patients with advanced non-squamous non-small cell lung cancer were enrolled. Patients with uncontrolled congestive heart failure and uncontrolled diabetes were excluded. The treatment regimen comprised carboplatin at an area under the curve of 5 mg/ml/min on day 1, paclitaxel at 90 mg/m(2) on days 1 and 8, and bevacizumab at 15 mg/kg on day 1 every 21 days for up to 4 cycles, followed by maintenance bevacizumab...
February 1, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28150073/first-in-human-phase-i-study-of-sor-c13-a-trpv6-calcium-channel-inhibitor-in-patients-with-advanced-solid-tumors
#9
S Fu, H Hirte, S Welch, T T Ilenchuk, T Lutes, C Rice, N Fields, A Nemet, D Dugourd, S Piha-Paul, V Subbiah, L Liu, J Gong, D Hong, J M Stewart
Introduction This was an open-label, dose escalation (3 + 3 design), Phase I study of SOR-C13 in patients with advanced tumors of epithelial origin. Primary objectives were to assess safety/tolerability and pharmacokinetics. Secondary goals were to assess pharmacodynamics and efficacy of SOR-C13. Methods SOR-C13 was administered IV QD on days 1-3 and 8-10 of a 21-day cycle. Doses were 2.75 and 5.5 mg/kg (20-min infusion) and 1.375, 2.75, 4.13 and 6.2 mg/kg (90-min infusion). Toxicity was assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4...
February 1, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28150072/surveillance-of-protocol-deviations-in-japanese-oncology-registration-trials-a-single-institute-experience
#10
Shinsuke Sasada, Nobuko Ushirozawa, Noriko Kobayashi, Yutaka Fujiwara, Kenji Tamura, Noboru Yamamoto
Background The contents and requirements of study protocols vary depending upon each clinical registration trial. This study aims to describe details of protocol deviations in Japanese oncology registration trials. Methods We reviewed deviation reports that were discussed by the Institutional Review Board between 2010 and 2015. Results A total of 499 clinical trials were performed, from which 967 deviations were reported. In the initial 3 years, 445 deviations occurred in 535 ongoing trials, while 522 deviations occurred in 876 trials in the subsequent 3 years...
February 1, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28144789/procaid-a-phase-i-clinical-trial-to-combine-the-akt-inhibitor-azd5363-with-docetaxel-and-prednisolone-chemotherapy-for-metastatic-castration-resistant-prostate-cancer
#11
Simon J Crabb, Alison J Birtle, Karen Martin, Nichola Downs, Ian Ratcliffe, Tom Maishman, Mary Ellis, Gareth Griffiths, Stuart Thompson, Lidia Ksiazek, Vincent Khoo, Robert J Jones
Background Docetaxel and prednisolone chemotherapy (DP) extends survival in metastatic castration resistant prostate cancer (mCRPC). However, emergent clinical resistance is almost inevitable. AKT pathway activation is highly prevalent in mCRPC contributing to disease progression and DP resistance. AZD5363 is a potent oral pan-AKT inhibitor with pre-clinical data indicating activity in mCRPC and synergy with docetaxel. Methods This phase I trial was to determine an AZD5363 recommended phase II dose (RP2D) for combination with DP...
February 1, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28138829/metabolism-and-disposition-of-the-anticancer-quinolone-derivative-vosaroxin-a-novel-inhibitor-of-topoisomerase-ii
#12
C M Nijenhuis, L Lucas, H Rosing, A D R Huitema, M Mergui-Roelvink, G C Jamieson, J A Fox, D R Mould, J H M Schellens, J H Beijnen
Background Vosaroxin is a first-in-class anticancer quinolone derivative that is being investigated for patients with relapsed or refractory acute myeloid leukemia (AML). The primary objective of this study was to quantitatively determine the pharmacokinetics of vosaroxin and its metabolites in patients with advanced solid tumors. Methods This mass balance study investigated the pharmacokinetics (distribution, metabolism, and excretion) of vosaroxin in cancer patients after a single dose of 60 mg/m(2 14)C-vosaroxin, administered as short intravenous injection...
January 31, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28138828/phase-i-ii-study-of-docetaxel-combined-with-resminostat-an-oral-hydroxamic-acid-hdac-inhibitor-for-advanced-non-small-cell-lung-cancer-in-patients-previously-treated-with-platinum-based-chemotherapy
#13
Yuichi Tambo, Yukio Hosomi, Hiroshi Sakai, Naoyuki Nogami, Shinji Atagi, Yasutsuna Sasaki, Terufumi Kato, Toshiaki Takahashi, Takashi Seto, Makoto Maemondo, Hiroshi Nokihara, Ryo Koyama, Kazuhiko Nakagawa, Tomoya Kawaguchi, Yuta Okamura, Osamu Nakamura, Makoto Nishio, Tomohide Tamura
Objectives To determine the recommended dose and efficacy/safety of docetaxel combined with resminostat (DR) in non-small cell lung cancer (NSCLC) patients with previous platinum-based chemotherapy. Materials and Methods A multicenter, open-label, phase I/II study was performed in Japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy. The recommended phase II dose was determined using a standard 3 + 3 dose design in phase I part. Resminostat was escalated from 400 to 600 mg/day and docetaxel fixed at 75 mg/m(2)...
January 30, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28124197/gemcitabine-and-s-1-versus-gemcitabine-and-cisplatin-treatment-in-patients-with-advanced-biliary-tract-cancer-a-multicenter-retrospective-study
#14
Naminatsu Takahara, Hiroyuki Isayama, Yousuke Nakai, Takashi Sasaki, Kazunaga Ishigaki, Kei Saito, Dai Akiyama, Rie Uchino, Suguru Mizuno, Hiroshi Yagioka, Hirofumi Kogure, Osamu Togawa, Saburo Matsubara, Yukiko Ito, Nobuo Toda, Minoru Tada, Kazuhiko Koike
Objective This study aimed to compare the safety and efficacy of the combination therapy of gemcitabine and S-1 (GS) versus gemcitabine and cisplatin (GC) in patients with advanced biliary tract cancer (BTC). Methods In this multicenter retrospective cohort study, a total of 212 patients with advanced BTC receiving GS (n = 125) or GC (n = 87) between July 2006 and August 2015 were analyzed. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective tumor response, and safety...
January 26, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28120180/a-truncated-apoptin-protein-variant-selectively-kills-cancer-cells
#15
Santiago Ruiz-Martínez, Jessica Castro, Maria Vilanova, Marta Bruix, Douglas V Laurents, Marc Ribó, Antoni Benito
Apoptin is a nonstructural protein encoded by one of the three open reading frames of the chicken anemia virus genome. It has attracted a great deal of interest due to its ability to induce apoptosis in multiple transformed and malignant mammalian cell lines without affecting primary and non-transformed cells. However, the use of Apoptin as an anticancer drug is restricted by its strong tendency to aggregate. A number of methods to overcome this problem have been proposed, including transduction techniques to deliver the Apoptin gene into tumor cells, but all such methods have certain drawbacks...
January 24, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28111728/pharmacokinetics-and-excretion-of-14-c-plitidepsin-in-patients-with-advanced-cancer
#16
L van Andel, S Fudio, H Rosing, S Munt, B Miguel-Lillo, I González, M M Tibben, N de Vries, A H M de Vries Schultink, J H M Schellens, J H Beijnen
Plitidepsin (Aplidin®) is a marine-derived anticancer compound currently investigated in phase III clinical trials. This article describes the distribution, metabolism and excretion of this novel agent and it mainly aims to identify the major routes of elimination. Six subjects were enrolled in a mass balance study during which radiolabelled plitidepsin was administered as a 3-h intravenous infusion. Blood samples were taken and urine and faeces were collected. Total radioactivity (TRA) analysis using Liquid Scintillation Counting (LSC) was done to determine the amount of radioactivity excreted from the body and plitidepsin concentrations in whole blood, plasma and urine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays...
January 23, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28111727/a-phase-1-study-of-the-pharmacokinetics-of-nucleoside-analog-trifluridine-and-thymidine-phosphorylase-inhibitor-tipiracil-components-of-tas-102-vs-trifluridine-alone
#17
James M Cleary, Lee S Rosen, Kenichiro Yoshida, Drew Rasco, Geoffrey I Shapiro, Weijing Sun
Background Trifluridine, a thymidine-based chemotherapeutic, has limited bioavailability after clinical administration as it is rapidly degraded via thymidine phosphorylase. An oral combination tablet combines trifluridine with a potent thymidine phosphorylase inhibitor, tipiracil hydrochloride. This study's objective was to evaluate whether trifluridine/tipiracil (TAS-102) administration increases trifluridine exposure vs trifluridine alone. Methods This open-label pharmacokinetic study randomly assigned patients with advanced solid tumors into two groups...
January 23, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28111726/ganetespib-overcomes-resistance-to-parp-inhibitors-in-breast-cancer-by-targeting-core-proteins-in-the-dna-repair-machinery
#18
Juhong Jiang, Yuanzhi Lu, Zhi Li, Liping Li, Daoli Niu, Wenwei Xu, Jing Liu, Lin Fu, Ziqing Zhou, Yingying Gu, Fen Xia
DNA damage repair plays essential roles in drug resistance, especially resistance to Poly (ADP-ribose) polymerase (PARP) inhibitors in the clinic. A subset of DNA repair proteins such as Breast cancer gene 1 (BRCA1), BRCA2 and RecA homolog (RAD51) are client proteins of heat shock protein 90 (Hsp90). Clearance of these DNA repair proteins by inhibition of Hsp90 is a promising strategy for overcoming resistance to PARP inhibitors. Here we report the pharmacological analysis of the highly potent second-generation Hsp90 inhibitor, ganetespib...
January 23, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28105566/phase-i-study-of-lurbinectedin-a-synthetic-tetrahydroisoquinoline-that-inhibits-activated-transcription-induces-dna-single-and-double-strand-breaks-on-a-weekly-%C3%A3-2-every-3-week-schedule
#19
Antonio Jimeno, Manish R Sharma, Sergio Szyldergemajn, Lia Gore, David Geary, Jennifer R Diamond, Carlos Fernandez Teruel, Arturo Soto Matos-Pita, Jorge Luis Iglesias, Martin Cullell-Young, Mark J Ratain
Background Lurbinectedin administered as a 1-h intravenous infusion every 3 weeks induces neutropenia, with the nadir usually occurring during the second week. This phase I study evaluated an alternative lurbinectedin dosing schedule consisting of a 1-h infusion on days 1 and 8 every 3 weeks. Patients and methods Twenty-one patients with advanced cancer received lurbinectedin using a standard cohort dose escalation design. Results Three dose levels of 3, 4, and 5 mg of lurbinectedin were explored. The recommended phase II dose was 5 mg, with 3 of 13 patients having dose-limiting toxicity (DLT), although grade 4 neutropenia occurred in 50% of patients...
January 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28102465/risks-and-benefits-of-phase-i-liver-dysfunction-studies-should-patients-with-severe-liver-dysfunction-be-included-in-these-trials
#20
Christos Fountzilas, Selena Stuart, Brian Hernandez, Elizabeth Bowhay-Carnes, Joel Michalek, John Sarantopoulos, Anand Karnad, Sukeshi Patel, Steven Weitman, Devalingam Mahalingam
Introduction The goal of organ dysfunction Phase I trials is to characterize the safety and pharmacokinetics of novel agents in cancer patients with liver or kidney dysfunction, but the clinical benefit is not well established. Methods We reviewed 170 patients across 15 liver dysfunction studies at our institution, grouped based on the NCI-Organ Dysfunction Working Group criteria or Child-Pugh Score. Results The median survival for the entire cohort was two months and just one month amongst patients with severe liver dysfunction...
January 19, 2017: Investigational New Drugs
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