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Investigational New Drugs

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https://www.readbyqxmd.com/read/29766337/a-phase-i-trial-to-determine-safety-and-pharmacokinetics-of-aslan002-an-oral-met-superfamily-kinase-inhibitor-in-patients-with-advanced-or-metastatic-solid-cancers
#1
Aflah Roohullah, Adam Cooper, Anna J Lomax, Jennifer Aung, Alan Barge, Lilian Chow, Mark McHale, Jayesh Desai, James R Whittle, Ben Tran, Paul de Souza, Lisa G Horvath
Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was conducted to determine the safety and pharmacokinetics of ASLAN-002 in patients with advanced cancer. Methods Patients with advanced or metastatic solid tumours, who had progressed on standard therapy or for whom standard therapy was not known, were administered ASLAN-002 orally...
May 16, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29761244/copper-tolfenamic-acid-evaluation-of-stability-and-anti-cancer-activity
#2
Myrna Hurtado, Umesh T Sankpal, Jaya Chhabra, Deondra T Brown, Rajasekhar Maram, Rafid Patel, Raj K Gurung, Jerry Simecka, Alvin A Holder, Riyaz Basha
The non-steroidal anti-inflammatory drug, Tolfenamic acid (TA) acts as an anti-cancer agent in several adult and pediatric cancer models. Copper (Cu) is an important element with multiple biological functions and has gained interest in medical applications. Recently, [Cu(TA)2 (bpy)] (Cu-TA) has been synthesized in order to enhance therapeutic activity. In this study, we synthesized Cu-TA using an established method, characterized it by UV visible spectroscopy and Fourier-transform infrared spectroscopy (FTIR), and tested its anti-cancer activity using twelve cell lines representing various cancers, such as Ewing sarcoma, glioblastoma, medulloblastoma, neuroblastoma, pancreatic and prostate...
May 15, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29728897/translational-pk-pd-modeling-analysis-of-mcla-128-a-her2-her3-bispecific-monoclonal-antibody-to-predict-clinical-efficacious-exposure-and-dose
#3
Aurelia H M de Vries Schultink, Robert P Doornbos, Alexander B H Bakker, Kees Bol, Mark Throsby, Cecile Geuijen, David Maussang, Jan H M Schellens, Jos H Beijnen, Alwin D R Huitema
Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study. Methods A PK-PD model was developed based on PK data from cynomolgus monkeys and tumor growth data from a mouse JIMT-1 xenograft model...
May 5, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29725881/a-multicentre-open-label-phase-ii-study-of-irinotecan-capecitabine-xeloda%C3%A2-and-oxaliplatin-ixo-as-first-line-treatment-in-patients-with-metastatic-gastric-or-gastroesophageal-junction-gej-adenocarcinoma
#4
Arthur Lui, Karen Mulder, Christine Brezden-Masley, Michael Vickers, Jose Monzon, Hagen Kennecke, Rakesh Goel, Larissa Vos, Sunita Ghosh, Horia Marginean, Anthony Fields, Jean Maroun, Jennifer Spratlin
Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m2 & I-160 mg/m2 IV, Day 2-15 X-1900 mg/m2 /day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m2 & I-120 mg/m2 IV, Day 2-15 X-1425 mg/m2 /day PO divided doses)...
May 4, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29721756/successful-oral-desensitization-with-osimertinib-following-osimertinib-induced-fever-and-hepatotoxicity-a-case-report
#5
Ryosuke Hirabayashi, Daichi Fujimoto, Yukari Satsuma, Masaki Hirabatake, Keisuke Tomii
Osimertinib is a standard second-line therapy for patients who develop EGFR Thr790Met resistance mutation after treatment with first-line epidermal growth factor receptor tyrosine kinase inhibitors. Although no other effective targeted treatment option exists for these patients, osimertinib might be permanently discontinued owing to the onset of severe drug-induced toxicities like hepatotoxicity. Herein, we report a case of successful oral desensitization with osimertinib after the patient developed osimertinib-induced fever and hepatotoxicity...
May 2, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29721755/human-acute-myeloid-leukemia-cells-express-neurokinin-1-receptor-which-is-involved-in-the-antileukemic-effect-of-neurokinin-1-receptor-antagonists
#6
A Molinos-Quintana, P Trujillo-Hacha, J I Piruat, J A Bejarano-García, E García-Guerrero, J A Pérez-Simón, Miguel Muñoz
The substance P/neurokinin-1 receptor system has been implicated in tumor cell proliferation. Neurokinin-1 receptor has been identified in different solid tumors but not frequently in hematopoietic malignant cells. We investigated the presence of the Neurokinin-1 receptor in acute myeloid leukemia cell lines (KG-1 and HL-60), demonstrating that acute myeloid leukemia cell lines overexpress the truncated Neurokinin-1 receptor isoform compared with lymphocytes from healthy donors. Using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) method, we demonstrated that substance P induced cell proliferation in both acute myeloid leukemia cell lines...
May 2, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29717400/crizotinib-induced-simultaneous-multiple-cardiac-toxicities
#7
Takuya Oyakawa, Nao Muraoka, Kei Iida, Masatoshi Kusuhara, Takahisa Kawamura, Tateaki Naito, Toshiaki Takahashi
Crizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricular fibrillation, and pericarditis simultaneously. The cardiotoxicity of crizotinib can sometimes be simultaneous; thus, intensive observation is needed.
May 2, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29696509/inhibiting-il-2-signaling-and-the-regulatory-t-cell-pathway-using-computationally-designed-peptides
#8
Tammy Price-Troska, Zhi-Zhang Yang, David Diller, Alexander Bayden, Mark Jarosinski, Joseph Audie, Stephen M Ansell
Background Increased serum levels of soluble interleukin-2 (IL-2) receptor alpha (sIL-2Rα) are an indicator of poor prognosis in patients with B-cell non-Hodgkin lymphoma (NHL). By binding to IL-2, sIL-2Rα upregulates Foxp3 expression and induces the development of regulatory T (Treg ) cells. Methods To inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of Foxp3 and decreasing Treg cell numbers, we developed peptides by structure-based computational design to disrupt the interaction between IL-2 and sIL-2Rα...
April 26, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29667135/optimising-intratumoral-treatment-of-head-and-neck-squamous-cell-carcinoma-models-with-the-diterpene-ester-tigilanol-tiglate
#9
Catherine M E Barnett, Natasa Broit, Pei-Yi Yap, Jason K Cullen, Peter G Parsons, Benedict J Panizza, Glen M Boyle
The five-year survival rate for patients with head and neck squamous cell carcinoma (HNSCC) has remained at ~50% for the past 30 years despite advances in treatment. Tigilanol tiglate (TT, also known as EBC-46) is a novel diterpene ester that induces cell death in HNSCC in vitro and in mouse models, and has recently completed Phase I human clinical trials. The aim of this study was to optimise efficacy of TT treatment by altering different administration parameters. The tongue SCC cell line (SCC-15) was identified as the line with the lowest efficacy to treatment...
April 18, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29667134/two-phase-i-pharmacokinetic-and-pharmacodynamic-studies-of-dfp-10917-a-novel-nucleoside-analog-with-14-day-and-7-day-continuous-infusion-schedules
#10
Kamalesh Sankhala, Chris H Takimoto, Alain C Mita, Henry Xiong, Jordi Rodón, Amir Mehrvarz Sarshekeh, K Burns, Kenzo Iizuka, Scott Kopetz
Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917...
April 18, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29667133/unique-characteristics-of-regulatory-approval-and-pivotal-studies-of-orphan-anticancer-drugs-in-japan
#11
Hiroki Nakayama, Katsura Tsukamoto
The approval of orphan anticancer drugs has increased, with the number exceeding that of non-orphan drugs in Japan in recent years. Although orphan anticancer drugs may have unique characteristics due to their rarity, these have not been fully characterized. We investigated anticancer drugs approved in Japan between April 2004 and November 2017 to reveal the characteristics of regulatory approval and pivotal studies on orphan anticancer drugs compared to non-orphan drugs. The median regulatory review time and number of patients in pivotal studies on orphan anticancer drugs (281...
April 17, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29637471/a-multi-arm-phase-i-dose-escalating-study-of-an-oral-notch-inhibitor-bms-986115-in-patients-with-advanced-solid-tumours
#12
Kyaw L Aung, Anthony B El-Khoueiry, Karen Gelmon, Ben Tran, Gaurav Bajaj, Bing He, Tian Chen, Lili Zhu, Sharath Poojary, Shashwati Basak, Zhenhao Qi, Anna Spreafico, Bruce S Fischer, Jayesh Desai
Background Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling. Method Two dose escalation schedules (Arm-A continuous daily schedule and Arm-B intermittent 2 times weekly schedule) of BMS-986115 were evaluated in advanced solid tumour patients. The primary objective was to establish the safety, tolerability and Maximum Tolerated Dose (MTD) of BMS-986115...
April 10, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29623482/nivolumab-induced-acute-granulomatous-tubulointerstitial-nephritis-in-a-patient-with-gastric-cancer
#13
Yoshihisa Nakatani, Hisato Kawakami, Masashi Ichikawa, Sachiyo Yamamoto, Yasuo Otsuka, Akiko Mashiko, Yasutoshi Takashima, Akihiko Ito, Kazuhiko Nakagawa, Shuji Arima
We here report a case of nivolumab-induced acute granulomatous tubulointerstitial nephritis in a patient with gastric cancer. A 68-year-old woman with recurrent gastric cancer developed acute kidney injury associated with kidney enlargement and urinary leukocytes after 38 cycles of nivolumab treatment. A diagnosis of acute granulomatous tubulointerstitial nephritis was made based on kidney biopsy findings. Immunohistochemistry revealed expression of programmed cell death-ligand 1 (PD-L1) in degenerated epithelial cells of collecting tubules...
April 6, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29616439/nab-paclitaxel-plus-gemcitabine-versus-folfirinox-as-the-first-line-chemotherapy-for-patients-with-metastatic-pancreatic-cancer-retrospective-analysis
#14
Jihoon Kang, Inhwan Hwang, Changhoon Yoo, Kyu-Pyo Kim, Jae Ho Jeong, Heung-Moon Chang, Sang Soo Lee, Do Hyun Park, Tae Jun Song, Dong Wan Seo, Sung Koo Lee, Myung-Hwan Kim, Seung-Mo Hong, Sang Hyun Shin, Dae Wook Hwang, Ki Byung Song, Jae Hoon Lee, Song Cheol Kim, Baek-Yeol Ryoo
Purpose nab-paclitaxel plus gemcitabine (AG) and FOLFIRINOX have been established as standard first-line treatment in metastatic pancreatic cancer (mPC). We performed retrospective analysis comparing the efficacies of AG and FOLFIRINOX in daily practice setting. Materials and Methods We analyzed 308 patients who presented initially as mPC and received AG (n = 149) or FOLFIRINOX (n = 159) as first-line treatment between 2013 and 2016. Primary endpoints were progression-free survival (PFS) and overall survival (OS)...
April 3, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29611022/a-phase-i-open-label-two-stage-study-to-investigate-the-safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-the-oral-akt-inhibitor-gsk2141795-in-patients-with-solid-tumors
#15
Carol Aghajanian, Katherine M Bell-McGuinn, Howard A Burris, Lillian L Siu, Lee-Ann Stayner, Jennifer J Wheler, David S Hong, Carla Kurkjian, Shubham Pant, Ademi Santiago-Walker, Jennifer L Gauvin, Joyce M Antal, Joanna B Opalinska, Shannon R Morris, Jeffrey R Infante
Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week)...
April 3, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29607467/new-no-and-h2s-releasing-doxorubicins-as-targeted-therapy-against-chemoresistance-in-castration-resistant-prostate-cancer-in-vitro-and-in-vivo-evaluations
#16
Elisabetta Bigagli, Cristina Luceri, Maria De Angioletti, Konstantin Chegaev, Mario D'Ambrosio, Chiara Riganti, Elena Gazzano, Simona Saponara, Mariangela Longini, Francesca Luceri, Lorenzo Cinci
Chemotherapy for castration-resistant prostate cancer (CRPC) is only temporarily effective due to the onset of chemoresistance. We investigated the efficacy of NO- and H2S-releasing doxorubicins (NitDox and H2SDox) in overcoming drug resistance and evaluated their safety. New and innovative NO- and H2 S-releasing doxorubicins (NitDox and H2 SDox) showed a good intracellular accumulation and high cytotoxic activity in vitro in an androgen-independent and doxorubicin-resistant DU-145 prostate cancer cell line...
April 2, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29607466/autophagy-inhibition-improves-the-chemotherapeutic-efficacy-of-cruciferous-vegetable-derived-diindolymethane-in-a-murine-prostate-cancer-xenograft-model
#17
Hossam Draz, Alexander A Goldberg, Emma S Tomlinson Guns, Ladan Fazli, Stephen Safe, J Thomas Sanderson
Prostate cancer is the second leading cause of cancer-related deaths in men in North America and there is an urgent need for development of more effective therapeutic treatments against this disease. We have recently shown that diindolylmethane (DIM) and several of its halogenated derivatives (ring-DIMs) induce death and protective autophagy in human prostate cancer cells. However, the in vivo efficacy of ring-DIMs and the use of autophagy inhibitors as adjuvant therapy have not yet been studied in vivo. The objective of this study was to determine these effects on tumor growth in nude CD-1 mice bearing bioluminescent androgen-independent PC-3 human prostate cancer cells...
April 2, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29607465/sirolimus-enhances-remission-induction-in-patients-with-high-risk-acute-myeloid-leukemia-and-mtorc1-target-inhibition
#18
Margaret T Kasner, Rosemarie Mick, Grace R Jeschke, Matthew Carabasi, Joanne Filicko-O'Hara, Neal Flomenberg, Noelle V Frey, Elizabeth O Hexner, Selina M Luger, Alison W Loren, James K Mangan, John L Wagner, Mark Weiss, Martin Carroll, Alexander E Perl
Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML...
April 2, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29594878/acquired-resistance-to-an-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitor-egfr-tki-in-an-uncommon-g719s-egfr-mutation
#19
Atsushi Osoegawa, Takafumi Hashimoto, Yohei Takumi, Miyuki Abe, Tomonori Yamada, Ryoji Kobayashi, Michiyo Miyawaki, Hideya Takeuchi, Tatsuro Okamoto, Kenji Sugio
Background Acquired resistance (AR) to an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is a common event, and several underlying mechanisms, including T790 M, MET amplification and PTEN downregulation, have been reported for the common EGFR mutations. EGFR G719X is an uncommon mutation that has been reported to show sensitivity to EGFR-TKIs. However, no established cell lines harboring the EGFR G719X have been reported in the literature. Materials and Methods G719S-GR cells were established from malignant pleural effusion of a patient whose tumor developed AR from gefitinib treatment...
March 28, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29572783/post-progression-survival-following-second-line-chemotherapy-in-patients-with-advanced-pancreatic-cancer-previously-treated-with-gemcitabine-a-meta-analysis
#20
REVIEW
Akiyoshi Kasuga, Yasuo Hamamoto, Ayano Takeuchi, Naohiro Okano, Kazuhiro Togasaki, Yu Aoki, Takeshi Suzuki, Kenta Kawasaki, Kenro Hirata, Yasutaka Sukawa, Takanori Kanai, Hiromasa Takaishi
Background Post-progression survival (PPS) could be a confounding element in interpreting data from clinical trials of second-line chemotherapy in patients with advanced pancreatic cancer (PC) previously treated with gemcitabine (GEM) because a recent meta-analysis of oxaliplatin combination therapy showed statistical heterogeneity for overall survival (OS) but not for progression-free survival (PFS). This study aimed to improve the understanding of the impact of PPS on OS in this setting. Methods Databases were searched to identify randomized controlled trials (RCTs) in the salvage setting...
March 23, 2018: Investigational New Drugs
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