Impact of neutrophil-to-lymphocyte ratio in patients with EGFR-mutant NSCLC treated with tyrosine kinase inhibitors
Conclusions NLR was a significant predictor of clinical efficacy and OS in NSCLC patients harboringEGFR mutations treated with gefitinib or erlotinib. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 10, 2020 Category: Drugs & Pharmacology Source Type: research

Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer
Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000  mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 7, 2020 Category: Drugs & Pharmacology Source Type: research

Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma
Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 5, 2020 Category: Drugs & Pharmacology Source Type: research

Clinical and radiation dose-volume factors related to pneumonitis after treatment with radiation and durvalumab in locally advanced non-small cell lung cancer
Conclusions Our study suggest that the severity of pneumonitis after durvalumab is unrelated to V20 or any of the clinical factors assessed in this study. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 3, 2020 Category: Drugs & Pharmacology Source Type: research

Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma
SummaryThis phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2  mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene...
Source: Investigational New Drugs - March 3, 2020 Category: Drugs & Pharmacology Source Type: research

Retrospective review of the activity and safety of apatinib and anlotinib in patients with advanced osteosarcoma and soft tissue sarcoma
Conclusion Both apatinib and anlotinib were effective for the treatment of sarcomas. However, the effectiveness of the two drugs and associated AEs varied based on the histological type of sarcoma. These differences may be due to their different sensitivities to targets such as RET, warranting further study. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 25, 2020 Category: Drugs & Pharmacology Source Type: research

Adjuvant pembrolizumab versus high-dose interferon α-2b for Chinese patients with resected stage III melanoma: a retrospective cohort study
Conclusions Adjuvant pembrolizumab appeared to be as effective as IFN- α-2b in prolonging RFS in Chinese patients with resected stage III melanoma. Adjuvant pembrolizumab was associated with a lower rate of treatment-related AEs than IFN-α-2b. A prospective study is needed to confirm the clinical benefit of adjuvant pembrolizumab and determine dependable biomarkers. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 18, 2020 Category: Drugs & Pharmacology Source Type: research

Anticancer activity of Turkish marine extracts: a purple sponge extract induces apoptosis with multitarget kinase inhibition activity
SummaryMarine natural products have drawn a great deal of attention as a vital source of new drugs for the last five decades. However, marine organisms in the seas surrounding Turkey (the Black Sea, the Aegean Sea and the Mediterranean Sea) haven ’t been yet extensively explored. In the present study, three marine organisms (Dysidea avara,Microcosmus sabatieri andEchinaster sepositus) were sampled from the Dardanelles (Turkish Straits System, Western Turkey) by scientific divers, transferred to the laboratory and then were extracted with 70% ethanol. The extracts were tested for their cytotoxic effect against K562, K...
Source: Investigational New Drugs - February 15, 2020 Category: Drugs & Pharmacology Source Type: research

Evaluating the antitumor activity of sphingosine-1-phosphate against human triple-negative breast cancer cells with basal-like morphology
SummarySphingosine-1-phosphate (S1P) is an important sphingolipid metabolite that regulates a wide range of physiological and pathophysiological processes. Our previous studies show that S1P selectively induces cell apoptosis in human breast cancer luminal A subtype cell line MCF7. In addition, S1P exhibits synergistic effects with chemotherapy drugs against both MCF7 and luminal B subtype cell line MDA-MB-361 at concentration in the high nM to low μM range. In the current study, we evaluated the effect of S1P on proliferation, apoptosis and cytotoxicity towards a panel of nine triple-negative breast cancer with basal-l...
Source: Investigational New Drugs - February 14, 2020 Category: Drugs & Pharmacology Source Type: research

Combating atherosclerosis with targeted Diosmin nanoparticles-treated experimental diabetes
SummaryDiabetes with poor glycemic control is accompanying with an increased risk of disease namely atherosclerotic cardiovascular. Diosmin (DSN), which is obtained from citrus fruit used to assist the treatment of hemorrhoids or chronic venous atherosclerosis diseases, has an antioxidant, anti-hyperglycemic and anti-inflammatory effect. DSN is characterized by poor water solubility which limits its absorption by the gastrointestinal tract. To overcome this limitation, this study was designed to increase DSN bioavailability and solubility, through its loading on polymeric matrix; hydroxypropyl starch (HPS) and Poly lactide...
Source: Investigational New Drugs - February 11, 2020 Category: Drugs & Pharmacology Source Type: research

Mirtazapine, a dopamine receptor inhibitor, as a secondary prophylactic for delayed nausea and vomiting following highly emetogenic chemotherapy: an open label, randomized, multicenter phase III trial
Conclusions This is the first randomized prospective study to show that adding mirtazapine has a substantial and statistically significant benefit with good tolerance in patients with breast cancer who have experienced delayed emesis following the same prior HEC. (Trial registration:ClinicalTrials.gov NCT02336750). (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 8, 2020 Category: Drugs & Pharmacology Source Type: research

Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia
AbstractIn acute myeloid leukemia (AML),TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients recei...
Source: Investigational New Drugs - February 4, 2020 Category: Drugs & Pharmacology Source Type: research

A Canadian cancer trials group phase IB study of durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4) given concurrently or sequentially in patients with advanced, incurable solid malignancies
Conclusions Concurrent administration of durvalumab and tremelimumab over 1  h is safe with a comparable PK profile to sequential administration. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 4, 2020 Category: Drugs & Pharmacology Source Type: research

Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cancer cells
SummaryProxalutamide is a newly developed androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (PCa) that has entered phase III clinical trials. In the present study, we intended to elucidate the antitumor efficacy of proxalutamide through the metabolomic profiling of PCa cells. Two AR-positive PCa cell lines and two AR-negative PCa cell lines were investigated. Cell viability assays based on ATP quantitation were conducted. LC-Q/TOF-MS was used to analyze intracellular metabolites before or after the administration of proxalutamide and two other clinical AR antagonists (bicalutamide ...
Source: Investigational New Drugs - February 1, 2020 Category: Drugs & Pharmacology Source Type: research

The structure and regulation of the E3 ubiquitin ligase HUWE1 and its biological functions in cancer
SummaryE3 ligases are a class of critical enzymes that can catalyse the transfer of ubiquitin (Ub) from an E2 enzyme to the substrate and are essential to cellular processes. The E3 ligase HUWE1 (also known as ARF-BP1, HECTH9, HSPC272, Ib772, LASU1, MULE, URE-B1, UREB1, and HECT, UBA and WWE domain-containing E3 ubiquitin protein ligase 1) is encoded by thehuwe1 gene. HUWE1 is a key regulator of the DNA damage response, transcription, autophagy, apoptosis and metabolism in a variety of cancers. Due to its pivotal role in conferring substrate specificity, HUWE1 has attracted enormous attention as a promising anticancer drug...
Source: Investigational New Drugs - February 1, 2020 Category: Drugs & Pharmacology Source Type: research

Association between metastatic sites and first-line pembrolizumab treatment outcome for advanced non –small cell lung cancer with high PD-L1 expression: a retrospective multicenter cohort study
SummaryAssociations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metas...
Source: Investigational New Drugs - January 27, 2020 Category: Drugs & Pharmacology Source Type: research

The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants
Conclusions Co-administration of itraconazole and lorlatinib increased the plasma exposure of lorlatinib relative to lorlatinib alone in healthy participants. Therefore, concomitant use of lorlatinib with strong CYP3A inhibitors should be avoided. If this combination is unavoidable, the starting dose of lorlatinib should be reduced from 100 mg to 75  mg. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 27, 2020 Category: Drugs & Pharmacology Source Type: research

MicroRNA-101-3p suppresses proliferation and migration in hepatocellular carcinoma by targeting the HGF/c-Met pathway
SummaryMicroRNAs are involved in each stage of tumor development. Activation of the hepatocyte growth factor (HGF)/c-Met axis facilitates the proliferation and migration of cancer cells, and the HGF/c-MET pathway provides potential targets for anticancer treatment. However, the interaction between HGF and miRNAs in hepatocellular carcinoma (HCC) remains unknown. Previous studies have shown that miR-101 is downregulated in various types of cancer and acts as a tumor suppressor, but the role of miR-101 in HCC has not yet been well defined. Here, we show that HGF is upregulated while microRNA-101-3p is significantly downregul...
Source: Investigational New Drugs - January 27, 2020 Category: Drugs & Pharmacology Source Type: research

A multi-center phase II trial evaluating the efficacy of palbociclib in combination with carboplatin for the treatment of unresectable recurrent or metastatic head and neck squamous cell carcinoma
Conclusion The combination of carboplatin and palbociclib is associated with significant treatment related toxicity and insufficient anti-tumor activity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 24, 2020 Category: Drugs & Pharmacology Source Type: research

Effective upfront treatment with low-dose ibrutinib for a patient with B cell prolymphocytic leukemia
SummaryB cell prolymphocytic leukemia (B-PLL) is a rare and aggressive disease that is associated with poor survival. Although initially asymptomatic patients do not require therapy, most patients will progress and inevitably require treatment. More than 50% of patients with B-PLL carry abnormalities in the TP53 tumor suppressor gene and/or complex karyotype and show resistance to conventional chemotherapy. The efficacy of ibrutinib, a B cell receptor inhibitor, for B-PLL with the TP53 abnormality as second-line therapy was recently demonstrated. We herein report that low-dose ibrutinib as upfront therapy induced a complet...
Source: Investigational New Drugs - January 22, 2020 Category: Drugs & Pharmacology Source Type: research

KRCA-0008 suppresses ALK-positive anaplastic large-cell lymphoma growth
SummaryAnaplastic lymphoma kinase (ALK), which belongs to the insulin receptor tyrosine kinase superfamily, plays an important role in nervous system development. Due to chromosomal translocations, point mutations, and gene amplification, constitutively activated ALK has been implicated in a variety of human cancers, including anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer, and neuroblastoma. We evaluated the anti-cancer activity of the ALK inhibitor KRCA-0008 using ALCL cell lines that express NPM (nucleophosmin)-ALK. KRCA-0008 strongly suppressed the proliferation and survival of NPM-ALK-positive ALCL ...
Source: Investigational New Drugs - January 20, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics of mitomycin-c lipidic prodrug entrapped in liposomes and clinical correlations in metastatic colorectal cancer patients
Conclusions PL-MLP treatment results in a substantial rate of disease stabilization in metastatic CRC, and prolonged survival in patients achieving stable disease. The correlation of neutrophil count and CEA level with pharmacokinetic parameters of MLP is an unexpected finding that needs further investigation. The association of long T ½ of MLP with stable disease and longer survival is consistent with an improved probability of disease control resulting from enhanced tumor localization of long-circulating liposomes and underscores the relevance of personalized pharmacokinetic evaluation in the use of nanomedicines....
Source: Investigational New Drugs - January 18, 2020 Category: Drugs & Pharmacology Source Type: research

A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer
We present the results of a phase I study of an oral selective gamma secretase (GS) inhibitor (critical to Notch signaling), RO4929097 in combination with neoadjuvant chemotherapy for operable triple negative breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) of RO4929097. Secondary objectives were to determine real-time pharmacokinetics of RO4929097 and paclitaxel, safety and pathologic (pCR) complete response to study treatment. Eligible patients, initiated carboplatin at AUC 6 administered intravenously (IV) on day 1, weekly paclitaxel at 80  mg/m2 IV and RO4929097 10 mg dai...
Source: Investigational New Drugs - January 17, 2020 Category: Drugs & Pharmacology Source Type: research

Effectiveness and safety of eribulin in Japanese patients with HER2-negative, advanced breast cancer: a 2-year post-marketing observational study in a real-world setting
Conclusions The effectiveness and safety results of eribulin as the first- or second-line treatment were favorable. Thus, these suggest eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer in Japan. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 16, 2020 Category: Drugs & Pharmacology Source Type: research

Acknowledgement of Reviewers 2019
(Source: Investigational New Drugs)
Source: Investigational New Drugs - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

Efficacy of different dosing schedules of capecitabine for metastatic breast cancer: a single-institution experience
Conclusions Our single institution experience showed that alternate dosing of capecitabine (biweekly, 28-day  cycle) may be a reasonable alternative to standard 21-day cycle with similar efficacy and fewer dose reductions. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 14, 2020 Category: Drugs & Pharmacology Source Type: research

Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies
Conclusions The tolerability and safety of aflibercept 2  mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 6, 2020 Category: Drugs & Pharmacology Source Type: research

Patient selection for a developmental therapeutics program using whole genome and Transcriptome analysis
Discussion When compared to single-gene DNA-based data alone, WGTA led to a 3-fold increase in treatment matching. In a setting where there is a high level of uncertainty around both the investigational agents and the biomarkers, more data are needed to fully evaluate the impact of routine use of WGTA. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 6, 2020 Category: Drugs & Pharmacology Source Type: research

NCI 6896: a phase I trial of vorinostat (SAHA) and isotretinoin (13-cis retinoic acid) in the treatment of patients with advanced renal cell carcinoma
SummaryPreclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumor sensitivity to retinoids and have synergistic anti-tumor activity when combined. We performed a Phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor vorinostat and isotretinoin in patients with advanced renal cell carcinoma (RCC). Vorinostat was administered at 300  mg orally twice daily in combination with escalating doses of isotretinoin for 3 consecutive days per week. A standard 3 + 3 dose escalation design was used. Dose limiting toxicities (DLT) were...
Source: Investigational New Drugs - January 3, 2020 Category: Drugs & Pharmacology Source Type: research

A phase 2 clinical trial of the heat shock protein 90 (HSP 90) inhibitor ganetespib in patients with refractory advanced esophagogastric cancer
In this study 26 eligible patients mainly: male 77%, median age 64 years were enrolled. The most common drug-related adverse events were diarrhea (77%), fatigue (65%), elevated ALKP (42%), and elevated AST (38%). The most common grade 3/4 AEs included: leucopenia (12%), fatigue (12%), diarrhea (8%), and el evated ALKP (8%). The ORR of 4% reflects the single patient of 26 who had a complete response and stayed on treatment for more than seventy (70) months. Median PFS and OS was 61 days (2.0 months), 94 days (3.1 months) respectively. Ganetespib showed manageable toxicity. While the study was termi ...
Source: Investigational New Drugs - January 2, 2020 Category: Drugs & Pharmacology Source Type: research

Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models
SummaryAcute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a n...
Source: Investigational New Drugs - December 23, 2019 Category: Drugs & Pharmacology Source Type: research

Evaluation of the potential effect of dacomitinib, an EGFR tyrosine kinase inhibitor, on ECG parameters in patients with advanced non-small cell lung cancer
SummaryPurpose The study evaluated the potential effect of dacomitinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, on the electrocardiogram (ECG) parameters in adult patients with advanced non-small cell lung cancer enrolled in a multicenter, open-label, phase 2 study.Methods Patients received dacomitinib for six doses of 45  mg every 12 h in a 7-day lead-in cycle (cycle 0), then 60 mg every 12 h for six doses in a 14-day cycle (cycle 1). Clock time-matched triplicate ECGs were performed at 0, 2, 4, 6, 8 and 10 h on day 1 (baseline) and day 4 of cycle 0, and prior to d...
Source: Investigational New Drugs - December 19, 2019 Category: Drugs & Pharmacology Source Type: research

Design, synthesis and cytotoxicity of the antitumor agent 1-azabicycles for chemoresistant glioblastoma cells
SummaryTwelve multi-functional pyrrolizidinones, indolizidinones and pyrroliazepinones were prepared from formal aza-[3  + 2] and aza-[3 + 3] cycloadditions of five- to seven-membered heterocyclic enaminones as diverse ambident electrophiles. The antitumor activity of these alkaloid-like compounds was investigated through an initial screening performed on human glioblastoma multiform (GBM) cell lines (GL-15, U251), on murine glioma cells line (C6) and on normal glial cells. Of the compounds tested, the new pyrrolo[1,2a]azepinone, [ethyl (3-oxo-1,2-diphenyl-6,7,8,9-tetrahydro-3H-pyrrolo[1,2a]azep...
Source: Investigational New Drugs - December 14, 2019 Category: Drugs & Pharmacology Source Type: research

Sorafenib may enhance antitumour efficacy in hepatocellular carcinoma patients by modulating the proportions and functions of natural killer cells
This study showed that sorafenib could affect the proportions and functions of peripheral CD56brightCD16− and CD56dimCD16+ NK cells, which was associated with the outcomes including OS of HCC patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 13, 2019 Category: Drugs & Pharmacology Source Type: research

Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors
SummaryPurpose Anticancer agents are known to increase cancer-associated thrombosis (CAT) onset. CAT onset rate is reported to be 1.92% in cisplatin-based therapy, 6.1% in paclitaxel plus ramucirumab combination therapy, and 11.9% in bevacizumab monotherapy. Because immune checkpoint inhibitors (ICIs) cause a sudden increase in T cell number, an association between administration of these drugs and increase in CAT incidence is likely. However, the extent to which ICI administration affects CAT incidence remains unclear. Further, risk factors for CAT incidence have not yet been identified. The present study investigated CAT...
Source: Investigational New Drugs - December 10, 2019 Category: Drugs & Pharmacology Source Type: research

W941, a new PI3K inhibitor, exhibits preferable anti-proliferative activities against nonsmall cell lung cancer with autophagy inhibitors
SummaryThe PI3K pathway is aberrantly activated in many cancers and plays a critical role in tumour cell proliferation and survival, making it a rational therapeutic target. In the present study, the effects and the underlying mechanism of a new PI3K inhibitor, W941, were investigated in non-small-cell lung cancer (NSCLC). The results of this study showed that W941 inhibited the growth of A549 and Hcc827 cells with IC50 values of 0.12 and 0.23  μM, respectively, and that W941 markedly inhibited the growth of A549 xenograft tumours in a nude mouse model without decreasing body weight. Western blotting assays showed ...
Source: Investigational New Drugs - December 10, 2019 Category: Drugs & Pharmacology Source Type: research

[HuArgI (co)-PEG5000]-induced arginine deprivation leads to autophagy dependent cell death in pancreatic cancer cells
In this study, we examined the sensitivity of pancreatic cancer cells to [HuArgI (Co)-PEG5000]-induced arginine deprivation as well as the mechanisms underlying deprivation-induced cell death. [HuArgI (Co)-PEG5000]-induced arginine deprivation was cytotoxic to all cell lines tested with IC50 values in the pM range at 72  h post-treatment. Three of the five cell lines were rescued by the addition of excess L-citrulline and expressed ASS1, indicating partial arginine auxotrophy. The remaining two cell lines, on the other hand, were not rescued by the addition of L-citrulline and did not express ASS1, indicating comp let...
Source: Investigational New Drugs - December 10, 2019 Category: Drugs & Pharmacology Source Type: research

Microarray expression profiles and bioinformatics analysis of mRNAs, lncRNAs, and circRNAs in the secondary temozolomide-resistant glioblastoma
AbstractTemozolomide is a first line anti-tumor drug used for the treatment of patients with Glioblastoma multiforme (GBM). However, the drug resistance to temozolomide limits its clinical application. Therefore, novel strategies to overcome chemoresistance are desperately needed for improved treatment of human GBM. Here, we simultaneously detected, for the first time, the expression profiles of mRNAs, lncRNAs, and circRNAs in three pairs of secondary temozolomide-resistant glioblastoma (STRG) and matched primary glioblastoma tissues by microarrays. Using these data, we discovered a total of 92 mRNA, 299 lncRNAs and 53 cir...
Source: Investigational New Drugs - December 10, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of TAS-115, a novel oral multi-kinase inhibitor, in patients with advanced solid tumors
SummaryTAS-115 is a novel MET, VEGFR, FMS and PDGFR inhibitor, developed to improve the continuity of drug administration with a relatively short half-life. We assessed its tolerability, safety, pharmacokinetics, efficacy, and pharmacodynamics in patients with solid tumors. This open-label, dose-escalation phase I study of TAS-115 consisted of three parts: part 1 (TAS-115 was administered orally once daily [SID]); part 2 and an expansion part (SID in a 5  days on/2 days off [5-on/2-off] schedule for 21 days per cycle). In part 1 (200–800 mg SID administered to 21 patients), systemic exposure after...
Source: Investigational New Drugs - December 10, 2019 Category: Drugs & Pharmacology Source Type: research

Combination of a novel microtubule inhibitor MBRI-001 and gemcitabine synergistically induces cell apoptosis by increasing DNA damage in pancreatic cancer cell lines
In this study, we aimed to investigate the anti-tumor effects of MBRI-001 in combination with GEM in BxPC-3 and MIA PaCa-2 human PC cell lines. In vitro and in vivo results indicate that MBRI-001 showed synergistic activity with GEM. GEM induced apoptosis by increasing DNA damage (phosphorylated core histone protein H2AX (γ-H2AX)), MBRI-001 activated mitochondrial-apopto tic pathway (cleaved poly-ADP ribose polymerase (PARP)). Thus, the combination of the two intensified both apoptosis and DNA damage and showed significantly superior anti-tumor activity compared to each agent alone. The adoption of combination of MBR...
Source: Investigational New Drugs - December 4, 2019 Category: Drugs & Pharmacology Source Type: research

Early depth of tumor shrinkage and treatment outcomes in non-small cell lung cancer treated using Nivolumab
SummaryBackground It would be useful to have criteria for predicting long-term treatment responses to immune checkpoint inhibitors (ICIs). Maximum depth of response correlates with treatment outcomes among patients receiving programmed death protein 1 axis inhibitors for non-small cell lung cancer (NSCLC). We investigated associations between early depth of response and survival outcomes among patients receiving nivolumab for NSCLC.Methods Using records from prospective observational cohorts, we identified 83 previously treated advanced patients with NSCLC who received nivolumab during 2016 –2017. Thirty-one patients...
Source: Investigational New Drugs - November 14, 2019 Category: Drugs & Pharmacology Source Type: research

Cellular uptake evaluation of pentagamaboronon-0 (PGB-0) for boron neutron capture therapy (BNCT) against breast cancer cells
In conclusion, the sugar formulations of PGB-0 only improved PGB-0 solubility but had no role in its cellular uptake. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 14, 2019 Category: Drugs & Pharmacology Source Type: research

Discovery and anticancer evaluation of a formononetin derivative against gastric cancer SGC7901 cells
Conclusion Derivative10 is an novel antitumor agent with potential for further clinical applications to treat gastric cancer.Graphical abstract (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 14, 2019 Category: Drugs & Pharmacology Source Type: research

A phase 1 dose-escalation study of checkpoint kinase 1 (CHK1) inhibitor prexasertib in combination with p38 mitogen-activated protein kinase (p38 MAPK) inhibitor ralimetinib in patients with advanced or metastatic cancer
Conclusions This study did not achieve its primary objective of establishing an RP2D of combination prexasertib + ralimetinib that could be safely administered to patients with advanced cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 9, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: a CCTG study
SummaryThe PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was admini...
Source: Investigational New Drugs - November 9, 2019 Category: Drugs & Pharmacology Source Type: research

The influence of direct-acting antivirals in hepatitis C virus related hepatocellular carcinoma after curative treatment
This study was done to elucidate the influence of direct-acting antiviral (DAA) agents on the recurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC (HCV-HCC) after curative therapies. HCV-HCC patients who received curative therapies and obtained a complete response were analyzed. From January 2017 to September 2017, 112 HCV-HCC patients received DAA and obtained a sustained virological response (SVR). From January 2006 to December 2014, another 345 HCV-HCC patients received peg-interferon-based treatment and 118 obtained SVR. From January 2012 to December 2016, 248 HCV-HCC patien...
Source: Investigational New Drugs - November 8, 2019 Category: Drugs & Pharmacology Source Type: research

Anticancer activities of vitamin K3 analogues
SummaryIn a previous study we reported on the synthesis of 1,4-naphthoquinone-sulfides by thiolation of 1,4-naphthohydroquinones with primary aryl and alkyl thiols using laccase as catalyst. These compounds were synthesized as Vitamin K3 analogues. Vitamin K3 (VK3; 2-methyl-1,4-naphthoquinone; menadione) is known to have potent anticancer activity. This investigation reports on the anticancer activity of these VK3 analogues against TK10 renal, UACC62 melanoma, MCF7 breast, HeLa cervical, PC3 prostate and HepG2 liver cancer cell lines to evaluate their cytostatic effects. A 1,4-naphthohydroquinone derivative exhibited poten...
Source: Investigational New Drugs - November 7, 2019 Category: Drugs & Pharmacology Source Type: research

Epigallocatechin-3-gallate mouthwash protects mucosa from radiation-induced mucositis in head and neck cancer patients: a prospective, non-randomised, phase 1 trial
SummaryRadiation-induced oral mucositis has a dismal outcome with limited treatment options. We conducted a phase I study to evaluate the safety and preliminary efficacy of epigallocatechin-3-gallate (EGCG) mouthwash when given along with radiation in head and neck cancer. Patients with pathologically confirmed head and neck cancer were eligible for this study. EGCG mouthwash was administered at the assigned dosage level (starting at 440  μmol/L, three times a day) in a standard 3 + 3 dose escalation design. Mucosal toxicity, patient satisfaction, and mucositis-related pain (MTP) were assessed weekly....
Source: Investigational New Drugs - November 7, 2019 Category: Drugs & Pharmacology Source Type: research

7-Chloroquinoline-1,2,3-triazoyl carboxamides induce cell cycle arrest and apoptosis in human bladder carcinoma cells
In conclusion, QTCA-1 and QTCA-4 are promising candidates for inducing cytotoxicity, cell cycle arrest, and apoptosis in human bladder cancer cells. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 6, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1)
Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 30, 2019 Category: Drugs & Pharmacology Source Type: research