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Investigational New Drugs

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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
#1
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
#2
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
https://www.readbyqxmd.com/read/28102464/a-phase-i-and-pharmacokinetic-study-of-afilbercept-with-folfiri-comparison-of-chinese-and-caucasian-populations
#3
Jianming Xu, Yingxin Li, Xing Sun, Dongsheng Zhang, Rongrui Liu, Samira Ziti-Ljajic, Dongmei Shi, Fengying Xue, Nathalie Le Bail, Ruihua Xu
Background This study assessed the preliminary safety, pharmacokinetics (PK) and anti-tumor effects of aflibercept in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in Chinese patients with previously-treated advanced solid malignancies. Patients and Methods This open-label single-arm Phase I study conducted at two centers in China included adult (≥18 years) patients with metastatic or unresectable solid malignancies who had received ≥1 prior treatment. Patients received aflibercept 4 mg/kg IV on Day 1 followed by FOLFIRI over Days 1 and 2 every 2 weeks, and were assessed for safety, tumor response, PK parameters and immunogenicity...
January 19, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28091835/acknowledgement-of-reviewers-2016
#4
(no author information available yet)
No abstract text is available yet for this article.
January 14, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28070720/safety-tolerability-and-pharmacokinetics-of-the-fibroblast-growth-factor-receptor-inhibitor-azd4547-in-japanese-patients-with-advanced-solid-tumours-a-phase-i-study
#5
Hideo Saka, Chiyoe Kitagawa, Yoshihito Kogure, Yasuo Takahashi, Koshi Fujikawa, Tamotsu Sagawa, Satoru Iwasa, Naoki Takahashi, Taro Fukao, Catherine Tchinou, Dónal Landers, Yasuhide Yamada
Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization...
January 10, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28070719/sunitinib-paracetamol-sex-divergent-pharmacokinetics-and-tissue-distribution-drug-drug-interaction-in-mice
#6
Ming Hui Liew, Salby Ng, Chii Chii Chew, Teng Wai Koo, Yun Lee Chee, Evelyn Li-Ching Chee, Pilar Modamio, Cecilia Fernández, Eduardo L Mariño, Ignacio Segarra
The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC0→∞, 31% and 27% lower liver and kidney AUC0→∞ and 2...
January 9, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28070718/first-in-human-trial-of-an-anti-5t4-antibody-monomethylauristatin-conjugate-pf-06263507-in-patients-with-advanced-solid-tumors
#7
Geoffrey I Shapiro, Ulka N Vaishampayan, Patricia LoRusso, Jeremy Barton, Steven Hua, Steven D Reich, Ronald Shazer, Carrie T Taylor, Dawei Xuan, Hossein Borghaei
Background The antibody-drug conjugate PF-06263507 targets the cell-surface, tumor-associated antigen 5T4 and consists of a humanized IgG1 conjugated to the microtubule-disrupting agent monomethylauristatin-F by a non-cleavable maleimidocaproyl linker. In this first-in-human, dose-finding trial (NCT01891669), we evaluated safety, pharmacokinetics, and preliminary antitumor activity of PF-06263507 in pretreated patients with advanced solid tumors, unselected for 5T4 expression. starting at 0.05 mg/kg, with 25, 56, and 95% dose increments, depending on observed dose-limiting toxicities (DLTs), applying a modified continual reassessment method...
January 9, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28058624/zebrafish-phenotypic-screen-identifies-novel-notch-antagonists
#8
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
Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors...
January 5, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28054329/a-first-in-human-phase-1-study-of-epirubicin-conjugated-polymer-micelles-k-912-nc-6300-in-patients-with-advanced-or-recurrent-solid-tumors
#9
Hirofumi Mukai, Takahiro Kogawa, Nobuaki Matsubara, Yoichi Naito, Masaoki Sasaki, Ako Hosono
Background K-912 also known as NC-6300 is a novel epirubicin pro-drug conjugate developed using micellar nanoparticle technology. We conducted a first-in-human, Phase 1, open-label, non-randomized dose escalation study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of K-912 administered as monotherapy in patients with advanced or recurrent solid tumors. Methods Patients aged 41 to 72 years with histologically or cytologically confirmed advanced or recurrent malignant solid tumors either refractory to standard therapy or had no other viable treatment options were enrolled...
January 4, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28050790/first-in-human-study-of-the-antibody-dr5-agonist-ds-8273a-in-patients-with-advanced-solid-tumors
#10
Andres Forero, Johanna C Bendell, Prasanna Kumar, Linda Janisch, Michael Rosen, Qiang Wang, Catherine Copigneaux, Madhuri Desai, Giorgio Senaldi, Michael L Maitland
Background DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid tumors. Methods The study comprised dose escalation and dose expansion cohorts. The dose escalation cohorts intended to determine the safety and to identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and 24 mg/kg once every 3 weeks)...
January 3, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28025760/targeting-specificity-protein-1-transcription-factor-and-survivin-using-tolfenamic-acid-for-inhibiting-ewing-sarcoma-cell-growth
#11
Sagar Shelake, Umesh T Sankpal, W Paul Bowman, Matthew Wise, Anish Ray, Riyaz Basha
Transcription factor Specificity protein 1 (Sp1) and its downstream target survivin (inhibitor of apoptosis protein), play major roles in the pathogenesis of various cancers. Ewing Sarcoma (ES) is a common soft tissue/bone tumor in adolescent and young adults. Overexpression of survivin is also linked to the aggressiveness and poor prognosis of ES. Small molecule Tolfenamic acid (TA) inhibits Sp1 and survivin in cancer cells. In this investigation, we demonstrate a strategy to target Sp1 and survivin using TA and positive control Mithramycin A (Mit) to inhibit ES cell growth...
December 26, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/28004284/a-phase-i-study-of-tivantinib-in-combination-with-temsirolimus-in-patients-with-advanced-solid-tumors
#12
Christos E Kyriakopoulos, Amy M Braden, Jill M Kolesar, Jens C Eickhoff, Howard H Bailey, Jennifer Heideman, Glenn Liu, Kari B Wisinski
Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination...
December 21, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27975234/pharmacokinetics-and-derivation-of-an-anticancer-dosing-regimen-for-the-novel-anti-cancer-agent-isobutyl-deoxynyboquinone-ib-dnq-a-nqo1-bioactivatable-molecule-in-the-domestic-felid-species
#13
Alycen P Lundberg, Joshua M Francis, Malgorzata Pajak, Elizabeth I Parkinson, Kathryn L Wycislo, Thomas J Rosol, Megan E Brown, Cheryl A London, Levent Dirikolu, Paul J Hergenrother, Timothy M Fan
Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent...
December 14, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27928714/phase-i-study-of-nivolumab-an-anti-pd-1-antibody-in-patients-with-malignant-solid-tumors
#14
Noboru Yamamoto, Hiroshi Nokihara, Yasuhide Yamada, Takashi Shibata, Yosuke Tamura, Yoshitaka Seki, Kazunori Honda, Yuko Tanabe, Hiroshi Wakui, Tomohide Tamura
Background This study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and antitumor activity of single and multiple doses of nivolumab in Japanese patients with malignant solid tumors. Subjects and Methods This was an open-label, dose-escalation study in 17 patients with advanced solid tumors with a life expectancy of ≥3 months. Patients were observed for 3 weeks after a single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of nivolumab every 2 weeks until unacceptable toxicity or disease progression occurred...
December 8, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27917453/phase-i-study-of-mrx34-a-liposomal-mir-34a-mimic-administered-twice-weekly-in-patients-with-advanced-solid-tumors
#15
Muhammad S Beg, Andrew J Brenner, Jasgit Sachdev, Mitesh Borad, Yoon-Koo Kang, Jay Stoudemire, Susan Smith, Andreas G Bader, Sinil Kim, David S Hong
Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-in-human, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3 + 3 dose escalation trial...
December 5, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27909934/current-achievements-and-future-perspectives-of-metronomic-chemotherapy
#16
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
#17
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
#18
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
#19
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
#20
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
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