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Investigational New Drugs

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https://www.readbyqxmd.com/read/28424891/a-phase-i-dose-escalation-study-of-selumetinib-in-combination-with-erlotinib-or-temsirolimus-in-patients-with-advanced-solid-tumors
#1
Jeffrey R Infante, Roger B Cohen, Kevin B Kim, Howard A Burris, Gregory Curt, Ugochi Emeribe, Delyth Clemett, Helen K Tomkinson, Patricia M LoRusso
Background Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors...
April 19, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28417284/a-phase-i-dose-escalation-study-of-the-safety-and-pharmacokinetics-of-a-tablet-formulation-of-voxtalisib-a-phosphoinositide-3-kinase-inhibitor-in-patients-with-solid-tumors
#2
Janice M Mehnert, Gerald Edelman, Mark Stein, Heather Camisa, Joanne Lager, Jean-François Dedieu, Anne-Frédérique Ghuysen, Jyoti Sharma, Li Liu, Patricia M LoRusso
Background Voxtalisib, a PI3K/mTOR inhibitor, has shown antitumor activity in capsule formulation in patients with solid tumors. This Phase I study assessed safety and pharmacokinetics of voxtalisib administered as immediate-release tablets in patients with solid tumors (NCT01596270). Methods A "3 + 3" dose escalation design was used. Adverse events (AEs), pharmacokinetics (PK), food effect and tumor response were evaluated. Results Thirty-two patients received voxtalisib doses ranging from 50 mg to 70 mg once daily (QD) and 17 patients received voxtalisib doses ranging from 30 mg to 50 mg twice daily (BID), for two 28-day cycles...
April 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28417283/bis-anthracycline-wp760-abrogates-melanoma-cell-growth-by-transcription-inhibition-p53-activation-and-igf1r-downregulation
#3
Magdalena Olbryt, Aleksandra Rusin, Izabela Fokt, Anna Habryka, Patrycja Tudrej, Sebastian Student, Aleksander Sochanik, Rafał Zieliński, Waldemar Priebe
Anthracycline chemotherapeutics, e.g. doxorubicin and daunorubicin, are active against a broad spectrum of cancers. Their cytotoxicity is mainly attributed to DNA intercalation, interference with topoisomerase activity, and induction of double-stranded DNA breaks. Since modification of anthracyclines can profoundly affect their pharmacological properties we attempted to elucidate the mechanism of action, and identify possible molecular targets, of bis-anthracycline WP760 which previously demonstrated anti-melanoma activity at low nanomolar concentrations...
April 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28401366/resistance-to-immunotherapy-clouds-in-a-bright-sky
#4
REVIEW
Gérard Milano
Two major challenges persist for an optimal management of immunotherapy: i) identifying those patients who will benefit from this type of therapy, and ii) determining the biological, cellular and molecular mechanisms that trigger disease progression while on therapy. There is a consensual view in favor of standardizing practices currently used to measure programmed death ligand 1 (PD-L1) expression that relates to innate resistance. The tumor mutation landscape has been widely explored as a potential predictor of treatment efficacy...
April 12, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28396974/sarcopenic-overweight-is-associated-with-early-acute-limiting-toxicity-of-anti-pd1-checkpoint-inhibitors-in-melanoma-patients
#5
Heidelberger Valentine, Goldwasser François, Kramkimel Nora, Jouinot Anne, Huillard Olivier, Boudou-Rouquette Pascaline, Chanal Johan, Arrondeau Jennifer, Franck Nathalie, Alexandre Jérôme, Blanchet Benoît, Leroy Karen, Avril Marie-Françoise, Dupin Nicolas, Aractingi Sélim
Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed...
April 10, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28391576/phase-i-trial-and-pharmacokinetic-study-of-tanibirumab-a-fully-human-monoclonal-antibody-to-vascular-endothelial-growth-factor-receptor-2-in-patients-with-refractory-solid-tumors
#6
Su Jin Lee, Seon Young Lee, Weon Sup Lee, Jin San Yoo, Jong-Mu Sun, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Myung-Ju Ahn, Ho Yeong Lim, Won Ki Kang, Young Suk Park
Background Tanibirumab is a fully human monoclonal antibody to vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a first-in-human phase I study of tanibirumab in patients with solid tumors refractory to standard chemotherapy. Primary endpoints were evaluating safety, pharmacokinetics (PKs), estimating maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Methods We designed our study to escalate tanibirumab at 9 different dose levels with a 3 + 3 method and tanibirumab (1-28 mg/kg) was administered intravenously on D1, 8, 15 in 28-day courses...
April 8, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28389981/erratum-to-first-in-human-phase-i-study-of-sor-c13-a-trpv6-calcium-channel-inhibitor-in-patients-with-advanced-solid-tumors
#7
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
No abstract text is available yet for this article.
April 7, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28378257/new-doxorubicin-nanocarriers-based-on-cyclodextrins
#8
Maurizio Viale, Valentina Giglio, Massimiliano Monticone, Irena Maric, Giovanni Lentini, Mattia Rocco, Graziella Vecchio
Polymeric nanoparticles and fibrin gels (FBGs) are attractive biomaterials for local delivery of a variety of biotherapeutic agents, from drugs to proteins. We combined these different drug delivery approaches by preparing nanoparticle-loaded FBGs characterized by their intrinsic features of drug delivery rate and antiproliferative/apoptotic activities. Inclusion complexes of doxorubicin (DOXO) with oligomeric β-cyclodextrins (oCyD) functionalized with different functional groups were studied. These nanocarriers were able to interact with FBGs as shown by a decreased release rate of DOXO...
April 4, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28361276/aplastic-anemia-in-a-lung-adenocarcinoma-patient-receiving-pemetrexed
#9
Goushi Matama, Takaaki Tokito, Hiroaki Takeoka, Yuki Hiraoka, Norikazu Matsuo, Masayuki Nakamura, Hidenobu Ishii, Takashi Kinoshita, Koichi Azuma, Kazuhiko Yamada, Tomoaki Hoshino
Pemetrexed (PEM) is an antimetabolite drug that interferes with enzymes involved in DNA synthesis and also the folate-dependent metabolic processes necessary for DNA replication and homocysteine homeostasis. Continuation maintenance with PEM after induction therapy with PEM plus cisplatin has been the standard form of first-line chemotherapy for advanced non-squamous non-small cell lung cancer. The regimen has a low incidence of bone marrow suppression, and the incidences of anemia, leukopenia, neutropenia and thrombocytopenia exceeding grade 3 are less than 5%...
March 30, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28353123/a-phase-1-open-label-dose-escalation-study-to-investigate-the-safety-tolerability-and-pharmacokinetics-of-mg1102-apolipoprotein-a-kringle-v-in-patients-with-solid-tumors
#10
Gun Min Kim, Tony Reid, Sang Joon Shin, Sun Young Rha, Joong Bae Ahn, Sung Sil Lee, Hyun Cheol Chung
Purpose MG1102 is a potent inhibitor of angiogenesis in both in vitro and in vivo models. The purpose of the study was to investigate the safety and tolerability, pharmacokinetic (PK) profile, and preliminary antitumor efficacy of MG1102. Methods Patients with refractory solid tumors were eligible. Each patient received 1 dose of MG1102 followed by a 6-day rest period, during which they underwent PK assessments and safety monitoring. If the initial dose was tolerated, the patient continued with the 21-day treatment of MG1102 (5 days on, 2 days off for 3 weeks)...
March 28, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28353122/phase-ii-study-of-the-multikinase-inhibitor-of-angiogenesis-linifanib-in-patients-with-metastatic-and-refractory-colorectal-cancer-expressing-mutated-kras
#11
Emily Chan, Laura W Goff, Dana B Cardin, Kristin Ancell, Stephen James Smith, Jennifer G Whisenant, Fei Ye, Jordan D Berlin
Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF-inhibition continues to improve survival. Combining epidermal growth factor receptor monoclonal antibodies with standard frontline therapies have also improved clinical outcomes, yet the improved benefit is not observed in patients with mutant KRAS. Thus, an unmet medical need exists to develop additional therapeutic options for patients with KRAS mutant CRC...
March 28, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28349229/mpt0b002-a-novel-microtubule-inhibitor-downregulates-t315i-mutant-bcr-abl-and-induces-apoptosis-of-imatinib-resistant-chronic-myeloid-leukemia-cells
#12
Yi-Yen Yeh, Jing-Ping Liou, Yueh-Lun Lee, John Yi-Chung Lin, Huei-Mei Huang
Chronic myeloid leukemia (CML) is a hematopoietic malignancy caused by the constitutive activation of Bcr-Abl tyrosine kinase. The Bcr-Abl inhibitor imatinib and other second-generation tyrosine kinase inhibitors such as dasatinib and nilotinib have remarkable efficacy in CML treatment. However, gene mutation-mediated drug resistance remains a critical problem. Among point mutations, the Bcr-Abl T315I mutation confers resistance to these Bcr-Abl inhibitors. Previously, we have synthesized the compound (1-methyl-1H-indol-5-yl)-(3,4,5-trimethoxy-phenyl)-methanone (MPT0B002) as a novel microtubule inhibitor...
March 27, 2017: Investigational New Drugs
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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