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Investigational New Drugs

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
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
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
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
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
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
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
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
Nobuaki Mamesaya, Hirotsugu Kenmotsu, Mineo Katsumata, Takashi Nakajima, Masahiro Endo, Toshiaki Takahashi
We report a case of a 38-year-old woman who was diagnosed with stage IV lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790 M mutation on exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) following treatment with nivolumab, an anti-Programmed Cell Death 1 (anti-PD1) antibody. After initiating osimertinib treatment, the patient began to complain of low-grade fever and shortness of breath without hypoxemia, and her chest radiograph and a CT scan revealed a remarkable antitumor response, although faint infiltrations were observed in the bilateral lung field...
September 6, 2016: Investigational New Drugs
Hirofumi Mukai, Ken Kato, Taito Esaki, Shouzou Ohsumi, Yasuo Hozomi, Nobuaki Matsubara, Tetsuya Hamaguchi, Yasuhiro Matsumura, Rika Goda, Takayuki Hirai, Yoshihiro Nambu
Previous studies have established the rationale for NK105, a nanomicellar formulation of paclitaxel, administered every 3 weeks. The aim of this phase I study was to determine the recommended dose and pharmacokinetics of weekly administered NK105. NK105 was administered by a 30-min infusion once weekly for three consecutive weeks in each 4-week cycle. In the dose-escalation phase, three to seven patients with solid tumors were enrolled to each of the four dose levels (50-100 mg/m(2); n = 16). At a dose level of 100 mg/m(2), predefined dose-limiting toxicity (DLT) manifested in only one out of six evaluable patients, whereas a dose delay due to neutropenia during the first course occurred two patients...
September 5, 2016: Investigational New Drugs
Sarah B Whittle, Kalyani Patel, Linna Zhang, Sarah E Woodfield, Michael Du, Valeria Smith, Peter E Zage
Background High-risk neuroblastoma has poor outcomes with high rates of relapse despite aggressive treatment, and novel therapies are needed to improve these outcomes. Ponatinib is a multi-tyrosine kinase inhibitor that targets many pathways implicated in neuroblastoma pathogenesis. We hypothesized that ponatinib would be effective against neuroblastoma in preclinical models. Methods We evaluated the effects of ponatinib on survival and migration of human neuroblastoma cells in vitro. Using orthotopic xenograft mouse models of human neuroblastoma, we analyzed tumors treated with ponatinib for growth, gross and histologic appearance, and vascularity...
September 1, 2016: Investigational New Drugs
Nicole E Frank, Barry J Cusack, Todd T Talley, Gerald M Walsh, Richard D Olson
Purpose A novel doxorubicin (DOX) analog, 13-deoxy, 5-iminodoxorubicin (DIDOX), was synthesized to prevent quinone redox cycling and alcohol metabolite formation, two prevailing hypotheses of anthracycline cardiotoxicity. The chronic cardiotoxicity of DOX and DIDOX was compared. Since a recent hypothesis posits that DOX-induced chronic cardiotoxicity may be mediated by inhibition of the topoisomerase IIβ/DNA reaction, we also compared potency of DOX and DIDOX to inhibit topoisomerase IIβ decatenation of kinetoplast DNA (kDNA) (a series or interlocking small rings of DNA)...
August 31, 2016: Investigational New Drugs
Noboru Yamamoto, Yutaka Fujiwara, Kenji Tamura, Shunsuke Kondo, Satoru Iwasa, Yuko Tanabe, Atsushi Horiike, Noriko Yanagitani, Satoru Kitazono, Michiyasu Inatani, Jun Tanaka, Makoto Nishio
Pictilisib (GDC-0941) is an oral class I phosphatidylinositol-3-phosphate kinase inhibitor. This phase Ia/Ib study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of pictilisib in monotherapy or in combination with carboplatin-paclitaxel and bevacizumab (CP + BEV) in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer. A standard 3 + 3 dose escalation design was applied. In stage 1, 140, 260, or 340 mg/day of pictilisib was administered once daily to 12 patients with advanced solid tumors...
August 27, 2016: Investigational New Drugs
Sunil Parimi, Misha Eliasziw, Scott North, Marc Trudeau, Eric Winquist, Kim N Chi, Dean Ruether, Tina Cheng, Bernhard J Eigl
Background Docetaxel is a standard first-line treatment option for men with metastatic castration resistant prostate cancer (mCRPC). Sunitinib is attractive as a maintenance therapy due to its mechanism of action, oral route of administration, and acceptable toxicity profile. We designed a phase II study of sunitinib in patients with mCRPC who responded to docetaxel. Methods Patients with responding or stable disease at the completion of docetaxel treatment received 50 mg of sunitinib on 4 week on 2 week off cycles...
August 26, 2016: Investigational New Drugs
Samer Tabchi, Hampig Raphael Kourie, Joseph Kattan
After the massive approval of checkpoint inhibitors in the treatment of numerous malignancies and settings, checkpoint inhibitors-based combination therapies are emerging as a new therapeutic modality. Nivolumab and pembrolizumab (anti-PD1 agents) were recently approved as second-line treatment in NSCLC after progression on platinum-doublets. In parallel, targeting EGFR/ALK in NSCLC using tyrosine kinase inhibitors (TKI) demonstrated remarkable outcomes and was approved as standard treatment, in patients with EGFR mutation or ALK rearrangement...
August 25, 2016: Investigational New Drugs
Teresa Di Desidero, Lisa Derosa, Luca Galli, Paola Orlandi, Andrea Fontana, Anna Fioravanti, Riccardo Marconcini, Mario Giorgi, Beatrice Campi, Alessandro Saba, Sara Lucchesi, Renato Felipetto, Romano Danesi, Giulio Francia, Giacomo Allegrini, Alfredo Falcone, Guido Bocci
The aim of the present study was to evaluate clinical activity, and the pharmacodynamic and pharmacokinetic profiles, of oral metronomic vinorelbine (VNR) plus dexamethasone (DEX) in metastatic castration-resistant prostate cancer (mCRPC) patients. Fourty-one patients (92 % chemotherapy-resistant) received 30 mg/day VNR p.o. thrice a week plus 1 mg/day DEX p.o. until disease progression. Plasma soluble B cell antigen 7 homolog 3 (sB7-H3), vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1), were measured by ELISA...
August 24, 2016: Investigational New Drugs
Hiroto Ueda, Hidetoshi Hayashi, Keita Kudo, Masayuki Takeda, Kazuhiko Nakagawa
Clinical trials of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have shown that some patients receiving these agents develop severe hepatotoxicity that necessitates treatment cessation. Both drugs undergo extensive hepatic metabolism mediated predominantly by cytochrome P450 family enzymes. Afatinib is a second-generation, irreversible EGFR-TKI that competes with ATP for binding to EGFR and the related proteins HER2 and HER4 and whose major circulating metabolites are covalent drug-protein adducts...
August 23, 2016: Investigational New Drugs
Sumimasa Nagai, Keiya Ozawa
To reduce the delay in marketing authorization of drugs in Japan, four Japanese national projects were instituted. We examined all oncologic drugs for adult patients approved or discussed through these schemes, for the first time. All the data are publicly available. In total, 197 applications/demands (181 indications and 16 dosages/uses) were collected. As of December 31, 2015, 64 indications and 10 dosages/uses were approved as off-label drugs through these schemes without conducting additional registration trials in Japan...
August 19, 2016: Investigational New Drugs
Jinhyun Cho, Soomin Ahn, Kwai Han Yoo, Jung Han Kim, Sang-Hee Choi, Kee-Taek Jang, Jeeyun Lee
Overexpression of PD-L1 has been shown to be associated with better clinical responses to PD-1/PD-L1 blockade in melanoma. However, the utility of PD-L1 immunostaining as a predictive biomarker for anti-PD-1 treatment remains unclear, especially in melanoma of acral/mucosal origin. Materials and methods We collected and reviewed the medical records of 37 patients with metastatic melanoma who were treated with the anti-PD-1 antibodies pembrolizumab or nivolumab between January and December 2015. Patients with histologically diagnosed malignant melanoma and whose pretreatment tumor specimens were available for immunohistochemical staining of PD-L1 expression in tumor or immune cells were included...
August 4, 2016: Investigational New Drugs
Kathleen Dekeister, Emmanuelle Graillot, Mickaël Durbec, Jean-Yves Scoazec, Thomas Walter
No abstract text is available yet for this article.
July 30, 2016: Investigational New Drugs
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