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Investigational New Drugs

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https://www.readbyqxmd.com/read/28317088/phase-i-trial-of-the-oral-smoothened-inhibitor-sonidegib-in-combination-with-paclitaxel-in-patients-with-advanced-solid-tumors
#1
A Stathis, D Hess, R von Moos, K Homicsko, G Griguolo, M Joerger, M Mark, C J Ackermann, S Allegrini, C V Catapano, A Xyrafas, M Enoiu, S Berardi, P Gargiulo, C Sessa
Purpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1-28) in combination with paclitaxel 80 mg/m(2) on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4...
March 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28317087/imaging-and-clinicopathological-features-of-nivolumab-related-cholangitis-in-patients-with-non-small-cell-lung-cancer
#2
Hisato Kawakami, Junko Tanizaki, Kaoru Tanaka, Koji Haratani, Hidetoshi Hayashi, Masayuki Takeda, Ken Kamata, Mamoru Takenaka, Masatomo Kimura, Takaaki Chikugo, Takao Sato, Masatoshi Kudo, Akihiko Ito, Kazuhiko Nakagawa
Background Nivolumab demonstrates promising efficacy for the treatment of non-small cell lung cancer and other malignancies. The clinical benefit of nivolumab, however, may be hampered by specific immune-related adverse events (irAEs), and little is known regarding nivolumab-related cholangitis. Methods A computerized search of our clinical database identified 3 metastatic non-small cell lung cancer patients with nivolumab-related cholangitis. All patients were treated with intravenous nivolumab monotherapy (3...
March 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28315153/effects-of-histone-deacetylase-inhibitory-prodrugs-on-epigenetic-changes-and-dna-damage-response-in-tumor-and-heart-of-glioblastoma-xenograft
#3
Nataly Tarasenko, Abraham Nudelman, Gabriela Rozic, Suzanne M Cutts, Ada Rephaeli
The histone deacetylase (HDAC) inhibitory prodrugs of butyric (AN7) and valproic (AN446) acids, which release the active acids upon metabolic degradation, were studied examining their differential effects on the viability, HDAC inhibitory activity and the DNA damage response (DDR), in glioblastoma cell and normal human astrocytes (NHAs). In xenografts of glioblastoma, AN7 or AN446 given or the combination of each of them with Dox augmented the anticancer activity of Dox and protected the heart from its toxicity...
March 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28303530/a-randomized-open-label-multicenter-phase-ii-study-evaluating-the-efficacy-and-safety-of-bth1677-1-3-1-6-beta-glucan-imprime-pgg-in-combination-with-cetuximab-and-chemotherapy-in-patients-with-advanced-non-small-cell-lung-cancer
#4
M Thomas, P Sadjadian, J Kollmeier, J Lowe, P Mattson, J R Trout, M Gargano, M L Patchen, R Walsh, M Beliveau, J F Marier, N Bose, K Gorden, F Schneller
Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm (N=60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m(2) and subsequent doses 250 mg/m(2), weekly; carboplatin, 6 mg/mL/min AUC (area-under-the-curve) by Calvert formula, once each 3-week cycle [Q3W]); and paclitaxel, 200 mg/m(2), Q3W) or Control arm (N=30; cetuximab/carboplatin/paclitaxel as above)...
March 16, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28303529/lung-cancer-and-%C3%AE-glucans-review-of-potential-therapeutic-applications
#5
REVIEW
Raheleh Roudi, Shahla Roudbar Mohammadi, Maryam Roudbary, Monireh Mohsenzadegan
The potential of natural substances with immunotherapeutic properties has long been studied. β-glucans, a cell wall component of certain bacteria and fungi, potentiate the immune system against microbes and toxic substances. Moreover, β-glucans are known to exhibit direct anticancer effects and can suppress cancer proliferation through immunomodulatory pathways. Mortality of lung cancer has been alarmingly increasingly worldwide; therefore, treatment of lung cancer is an urgent necessity. Numerous researchers are now dedicated to using β-glucans as a therapy for lung cancer...
March 16, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28303528/human-mass-balance-study-and-metabolite-profiling-of-14-c-niraparib-a-novel-poly-adp-ribose-polymerase-parp-1-and-parp-2-inhibitor-in-patients-with-advanced-cancer
#6
Lotte van Andel, Z Zhang, S Lu, V Kansra, S Agarwal, L Hughes, M M Tibben, A Gebretensae, L Lucas, M J X Hillebrand, H Rosing, J H M Schellens, J H Beijnen
Niraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive, ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Significant improvements in PFS were seen in all patient cohorts regardless of biomarker status...
March 16, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28299514/prognostic-and-predictive-value-of-circulating-tumor-cells-and-cxcr4-expression-as-biomarkers-for-a-cxcr4-peptide-antagonist-in-combination-with-carboplatin-etoposide-in-small-cell-lung-cancer-exploratory-analysis-of-a-phase-ii-study
#7
Ravi Salgia, R Waide Weaver, Michael McCleod, John R Stille, S Betty Yan, Stephanie Roberson, John Polzer, Amy Flynt, Eyas Raddad, Victoria L Peek, Sameera R Wijayawardana, Suzane L Um, Steve Gross, Mark C Connelly, Carrie Morano, Madeline Repollet, Renouard Sanders, Kurt Baeten, David D'Haese, David R Spigel
Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome...
March 15, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28285369/diclofenac-sex-divergent-drug-drug-interaction-with-sunitinib-pharmacokinetics-and-tissue-distribution-in-male-and-female-mice
#8
Chii Chii Chew, Salby Ng, Yun Lee Chee, Teng Wai Koo, Ming Hui Liew, Evelyn Li-Ching Chee, Pilar Modamio, Cecilia Fernández, Eduardo L Mariño, Ignacio Segarra
Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC0→∞ 38% in plasma (p < 0.05) and 24% in liver (p < 0.001) and 23% in kidney (p < 0...
March 11, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28285368/risk-of-hypertension-with-ramucirumab-based-therapy-in-solid-tumors-data-from-a-literature-based-meta-analysis
#9
REVIEW
Giandomenico Roviello, Chiara Pacifico, Paola Corona, Daniele Generali
Ramucirumab is a monoclonal antibody against Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) approved for the treatment of several solid tumours. As shown in recent trials results, new-onset hypertension is one of the most frequent adverse events associated with ramucirumab therapy. Recent studies looked at the quantification of the risk of hypertension in patients receiving other anti-angiogenesis medications. We conducted a meta-analysis of randomized clinical trials with the aim to investigate the incidence and quantify the risk of new-onset hypertension of any grade in patients treated with ramucirumab...
March 11, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28283780/metabolic-carbonyl-reduction-of-anthracyclines-role-in-cardiotoxicity-and-cancer-resistance-reducing-enzymes-as-putative-targets-for-novel-cardioprotective-and-chemosensitizing-agents
#10
REVIEW
Kamil Piska, Paulina Koczurkiewicz, Adam Bucki, Katarzyna Wójcik-Pszczoła, Marcin Kołaczkowski, Elżbieta Pękala
Anthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to secondary alcohol metabolites (i.e. doxorubicinol, daunorubicinol) catalyzed by carbonyl reductases (CBR) and aldo-keto reductases (AKR). These metabolites are suspected to be more cardiotoxic than their parent compounds...
March 10, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28283779/phase-ib-study-of-the-mitochondrial-inhibitor-me-344-plus-topotecan-in-patients-with-previously-treated-locally-advanced-or-metastatic-small-cell-lung-ovarian-and-cervical-cancers
#11
Jennifer R Diamond, Barbara Goff, Martin D Forster, Johanna C Bendell, Carolyn D Britten, Michael S Gordon, Hani Gabra, David M Waterhouse, Mark Poole, D Ross Camidge, Erika Hamilton, Kathleen M Moore
Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m(2) on days 1, 8, and 15 of a 28 day cycle...
March 10, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28281183/a-phase-1b-dose-expansion-study-of-the-pan-class-i-pi3k-inhibitor-buparlisib-bkm120-plus-carboplatin-and-paclitaxel-in-pten-deficient-tumors-and-with-dose-intensified-carboplatin-and-paclitaxel
#12
Lillian M Smyth, Kelsey R Monson, Komal Jhaveri, Alexander Drilon, Bob T Li, Wassim Abida, Gopa Iyer, John F Gerecitano, Mrinal Gounder, James J Harding, Martin H Voss, Vicky Makker, Alan L Ho, Pedram Razavi, Alexia Iasonos, Philip Bialer, Mario E Lacouture, Jerrold B Teitcher, Joseph P Erinjeri, Nora Katabi, Matthew G Fury, David M Hyman
Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials...
March 9, 2017: Investigational New Drugs
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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/28150073/first-in-human-phase-i-study-of-sor-c13-a-trpv6-calcium-channel-inhibitor-in-patients-with-advanced-solid-tumors
#20
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
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