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Investigational New Drugs

Antonio Jimeno, Kathleen N Moore, Michael Gordon, Rashmi Chugh, Jennifer R Diamond, Raid Aljumaily, David Mendelson, Ann M Kapoun, Lu Xu, Robert Stagg, David C Smith
Purpose Navicixizumab (OMP-305B83) is a bispecific antibody that inhibits delta-like ligand 4 and vascular endothelial growth factor. This Phase 1a trial assessed escalating doses of navicixizumab in refractory solid tumors patients. Design A 3 + 3 dose escalation design was used followed by the treatment of additional patients in an expansion cohort. Study objectives were determination of the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, immunogenicity and efficacy. Results Sixty-six patients were treated once every 3 weeks in 8 dose-escalation cohorts (0...
September 19, 2018: Investigational New Drugs
Yuan Lu, Ang Li, Xiaofeng Lai, Jun Jiang, Lihong Zhang, Zhicheng Zhong, Wen Zhao, Ping Tang, Hu Zhao, Xinling Ren
Interstitial lung disease (ILD) is a rare but lethal adverse effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment. The specific mechanism of this disease is not fully understood. To systematically analyze genes associated with EGFR-TKI induced ILD, gene data of EGFR-TKI induced ILD were extracted initially using text mining, and then the intersection between genes from text mining and Gene Expression Omnibus (GEO) dataset was taken for further protein-protein interaction (PPI) analysis using String-bd database...
September 10, 2018: Investigational New Drugs
Lisa M Oppegard, Justine L Delgado, Chaitanya A Kulkarni, Tyrell R Towle, Delaney E Hart, Bridget P Williams, Sarah R C Lentz, Beverly J Norris, Craig M Flory, Robert J Schumacher, Daryl J Murry, Robert J Kerns, Hiroshi Hiasa
Fluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that target eukaryotic type IIA topoisomerases. Fluoroquinolones bind and stabilize type IIA topoisomerase-DNA covalent complexes that contain a double-strand break. This unique mode of action is referred to as 'topoisomerase poisoning'. We discovered that two novel fluoroquinolones having aryl functionality at the N-1 position, UITT-3-217 (217) and UITT-3-227 (227), could inhibit the catalytic activity of human topoisomerase II without stabilizing topoisomerase-DNA complexes, i...
September 10, 2018: Investigational New Drugs
Won Young Tak, Baek-Yeol Ryoo, Ho Yeong Lim, Do-Young Kim, Takuji Okusaka, Masafumi Ikeda, Hisashi Hidaka, Jong-Eun Yeon, Eishiro Mizukoshi, Manabu Morimoto, Myung-Ah Lee, Kohichiroh Yasui, Yasunori Kawaguchi, Jeong Heo, Sojiro Morita, Tae-You Kim, Junji Furuse, Kazuhiro Katayama, Takeshi Aramaki, Rina Hara, Takuya Kimura, Osamu Nakamura, Masatoshi Kudo
PURPOSE: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II...
September 10, 2018: Investigational New Drugs
Muhammed H Rahaman, Yingyi Yu, Longjin Zhong, Julian Adams, Frankie Lam, Peng Li, Ben Noll, Robert Milne, Jun Peng, Shudong Wang
Acute myeloid leukemia (AML) is the most common form of acute leukemia with dismal long-term prognosis with age. The most aggressive subtype of AML is MLL-AML that is characterized by translocations of the mixed-lineage leukemia gene (MLL) and resistance to conventional chemotherapy. Cyclin dependent kinase 9 (CDK9) plays a crucial role in the MLL-driven oncogenic transcription, and hence, inhibiting activity of CDK9 has been proposed as a promising strategy for treatment of AML. We investigated the therapeutic potential of CDKI-73, one of the most potent CDK9 inhibitors, against a panel of AML cell lines and samples derived from 97 patients...
September 8, 2018: Investigational New Drugs
Pedro C Barata, Matthew Cooney, Prateek Mendiratta, Allison Tyler, Robert Dreicer, Jorge A Garcia
Introduction Ketoconazole is CYP-17 inhibitor with demonstrated activity in men with castration-resistant prostate cancer (CRPC). Lenalidomide is an antiangiogenic and immunomodulatory agent with broad antitumor activity. We hypothesized that the modulation of the cellular immune response to apoptosis caused by ketoconazole may be increased with the addition of lenalidomide. Methods This is an open-label, non-randomized, single-arm phase II study evaluating the efficacy and safety of the combination of ketoconazole and lenalidomide in patients with CRPC...
September 6, 2018: Investigational New Drugs
Laura W Goff, Nilo Azad, Stacey Stein, Jennifer G Whisenant, Tatsuki Koyama, Ulka Vaishampayan, Howard Hochster, Roisin Connolly, Amy Weise, Patricia M LoRusso, Safia N Salaria, Wael El-Rifai, Jordan D Berlin
Overexpression and cellular mis-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death. Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window...
September 6, 2018: Investigational New Drugs
Khalid Jazieh, Julian Molina, Jacob Allred, Jun Yin, Joel Reid, Matthew Goetz, Vun-Sin Lim, Scott H Kaufmann, Alex Adjei
Introduction Based on preclinical cytotoxic synergy between tipifarnib and erlotinib, a phase I study of this combination was conducted in patients with advanced solid tumors to evaluate safety, tolerability, maximum tolerated dose (MTD) and preliminary evidence of efficacy. Methods Patient enrollment followed the traditional "3 + 3" dose escalation scheme, through 4 dose levels, ranging from tipifarnib 200 mg twice daily plus erlotinib 75 mg once daily to tipifarnib 300 mg twice daily plus erlotinib 150 mg once daily...
August 31, 2018: Investigational New Drugs
Lei Zhong, Shu Zhou, Rongsheng Tong, Jianyou Shi, Lan Bai, Yuxuan Zhu, Xingmei Duan, Wenzhao Liu, Jinku Bao, Lingyu Su, Qian Peng
Esophageal squamous cell carcinoma (ESCC) is one of the most serious life-threatening malignancies. Although chemotherapeutic targets and agents for ESCC have made much progress recently, the efficacy is still unsatisfactory. Therefore, there is still an unmet medical need for patients with ESCC. Here, we report the expression status of HDAC1 in human ESCC and matched paracancerous tissues, and the results indicated that HDAC1 was generally upregulated in ESCC specimens. Furthermore, we comprehensively assessed the anti-ESCC activity of a highly active HDAC1 inhibitor quisinostat...
August 31, 2018: Investigational New Drugs
Viviane A O Silva, Ana Laura V Alves, Marcela N Rosa, Larissa R V Silva, Matias E Melendez, Fernanda P Cury, Izabela N F Gomes, Aline Tansini, Giovanna B Longato, Olga Martinho, Bruno G Oliveira, Fernanda E Pinto, Wanderson Romão, Rosy I M A Ribeiro, Rui M Reis
Cervical cancer is the third most commonly diagnosed tumor type and the fourth cause of cancer-related death in females. Therapeutic options for cervical cancer patients remain very limited. Annona crassiflora Mart. is used in traditional medicine as antimicrobial and antineoplastic agent. However, little is known about its antitumoral properties. In this study the antineoplastic effect of crude extract and derived partitions from A. crassiflora Mart in cervical cancer cell lines was evaluated. The crude extract significantly alters cell viability of cervical cancer cell lines as well as proliferation and migration, and induces cell death in SiHa cells...
August 29, 2018: Investigational New Drugs
Charlée Nardin, Sophie Borot, Marie-Astride Beaudoin, Françoise Cattin, Eve Puzenat, Anne-Sophie Gauthier, Franck Schillo, Christophe Borg, François Aubin
The recent advent of immune checkpoint inhibitors (ICI), including anti-programmed cell death 1 protein (anti-PD-1) agents has revolutionized the therapeutic approach of metastatic malignancies. Yet, ICI can disrupt immune tolerance resulting in enhanced immune activation in normal tissues with significant toxicity. A dysregulated activation of T-cells directed to normal tissues stands as the main mechanism of immune-related adverse events (irAE). To date, only two cases of immune-related inflammatory orbitopathy related to anti-PD-1 agents have been reported...
August 25, 2018: Investigational New Drugs
Tycel Phillips, Paul M Barr, Steven I Park, Kathryn Kolibaba, Paolo F Caimi, Saurabh Chhabra, Edwin C Kingsley, Thomas Boyd, Robert Chen, Anne-Sophie Carret, Elaina M Gartner, Hong Li, Cindy Yu, David C Smith
Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg...
August 22, 2018: Investigational New Drugs
Yusuke Chihara, Koji Date, Yoshizumi Takemura, Nobuyo Tamiya, Yoshihito Kohno, Tatsuya Imabayashi, Yoshiko Kaneko, Tadaaki Yamada, Mikio Ueda, Taichiro Arimoto, Junji Uchino, Yoshinobu Iwasaki, Koichi Takayama
This phase I study was aimed at determining the maximum tolerated dose (MTD) and recommended dose (RD) for oral S-1 plus paclitaxel combination therapy in elderly patients with non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients (age, >70 years) with stage III/IV NSCLC were treated with paclitaxel intravenously at four dose levels (DLs), 60, 70, 80, and 90 mg/m2 , on day 1 and 8, and with S-1 (80 mg/m2 ) orally on days 1-14 every 3 weeks. MTD was defined as the dose at which two of the initial three patients experienced dose-limiting toxicities (DLTs)...
August 18, 2018: Investigational New Drugs
Mohammed Albatany, Susan Meakin, Robert Bartha
The response of tumor intracellular pH to a pharmacological challenge could help identify aggressive cancer. Chemical exchange saturation transfer (CEST) is an MRI contrast mechanism that is dependent on intracellular pH (pHi ). pHi is important in the maintenance of normal cell function and is normally maintained within a narrow range by the activity of transporters located at the plasma membrane. In cancer, changes in pHi have been correlated with both cell proliferation and cell death. Quercetin is a bioflavonoid and monocarboxylate transporter (MCT) inhibitor...
August 13, 2018: Investigational New Drugs
Ciara M Kelly, Alexander N Shoushtari, Li-Xuan Qin, Sandra P D'Angelo, Mark A Dickson, Mrinal M Gounder, Mary Louise Keohan, Chloe Mcfadyen, Ana Sjoberg, Samuel Singer, Ronald P DeMatteo, Sinchun Hwang, M H Heinemann, Jasmine H Francis, Cristina R Antonescu, Ping Chi, William D Tap
Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST...
August 13, 2018: Investigational New Drugs
Kota Itahashi, Toshio Shimizu, Takafumi Koyama, Shunsuke Kondo, Yutaka Fujiwara, Noboru Yamamoto
Background Systematic analyses regarding cancer types of patients enrolled in oncology phase I trials are scarce. The global distribution, time-dependent change, and regional differences were evaluated. Methods A systematic search of the PubMed database, in which all single-agent phase I trials permitting the enrollment of all-comer patients with any type of solid tumor published between January 1991 and December 2015 were specified, was performed. Trials expected to enroll specific patient populations were excluded according to predefined criteria...
August 7, 2018: Investigational New Drugs
Navid Sobhani, Daniele Generali, Alberto D'Angelo, Michele Aieta, Giandomenico Roviello
Castrate-Resistant Prostate-Cancer (CRPC) is one of the most common malignancies occurring in men. Unfortunately, even if several recently approved agents clinically improved the outcome of CRPC patients, none of these is curative especially for a splice version of the Androgen Receptor (AR) AR-V7, which is a variant of the receptor constitutively activated and does not require the presence of androgens for the activation AR down-stream pathways. Since high AR-V7 expression is one of the most common features of CRPC, targeting this receptor variant is considered as one of the most promising strategies for treating this disease...
August 7, 2018: Investigational New Drugs
Chongchong Wang, Juehua Jing, Li Cheng
Non-coding RNAs (ncRNAs) have been found to play essential roles in various physiological and pathological processes. The involvement of ncRNAs in the development of osteosarcoma (OS) has been explored in recent years. In this review, we summarize the functions and mechanisms of microRNA, lncRNA and circRNA in the initiation and progression of OS. We specifically focused on their potential application in the diagnosis, prognosis and therapy of OS. This summary of current knowledge on the involvement of ncRNAs in OS will not only aid comprehension of the complex processes of OS initiation and progression but also contribute to the exploration of ideal diagnostic biomarkers and therapeutic targets for OS patients...
August 6, 2018: Investigational New Drugs
James J Harding, Todd M Bauer, Daniel S W Tan, Philippe L Bedard, Jordi Rodon, Toshihiko Doi, Christian Schnell, Varsha Iyer, Fabienne Baffert, Rajkumar Radhakrishnan, Claire Fabre, Dejan Juric
Background CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle...
August 3, 2018: Investigational New Drugs
Hui Huang, Junxing Niu, Fei Wang, Lihong Hu, Qiang Yu
We investigated the function and molecular mechanisms of 2-desoxy-4β-propylcarbamate-pulchellin (P-13), a sesquiterpene lactone derivative of 2-desoxy-4-epi-pulchellin from the traditional Chinese medicinal herb Carpesium abrotanoides L, in regulating STAT3 signaling and cancer cell growth. We found that P-13 inhibited the IL-6-induced, as well as the constitutive, STAT3 activation in a dose and time-dependent manner. In vitro kinase activity analyses demonstrated that P-13 directly inhibited JAK2 kinase activity...
August 3, 2018: Investigational New Drugs
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