Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors
Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 2, 2017 Category: Drugs & Pharmacology Source Type: research

Systematic analysis reveals a lncRNA-mRNA co-expression network associated with platinum resistance in high-grade serous ovarian cancer
SummaryResistance to platinum-based chemotherapy is the major barrier to treating high-grade serous ovarian cancer (HGS-OvCa). To improve HGS-OvCa patient prognosis, it is critical to identify the underlying mechanisms that promote platinum resistance. The goal of the present study was to identify a lncRNA-mRNA co-expression network and key lncRNAs that predict resistance to platinum-based chemotherapy in ovarian cancer patients. By systematically analyzing the expression profiles of lncRNAs and mRNAs in HGS-OvCa samples from the Cancer Genome Atlas (TCGA), we revealed that lncRNAs play important roles in platinum resistan...
Source: Investigational New Drugs - October 30, 2017 Category: Drugs & Pharmacology Source Type: research

Ganoderic acid, lanostanoid triterpene: a key player in apoptosis
SummaryCancer is a multifactorial disease, causing behavioral and metabolic alterations, leading to uncontrolled cell proliferation with collateral weakening of immune system. Crucial balance between cell proliferation and cell death determines the fate of a cell, which might progress towards survival or apoptosis. Apoptosis is a complex, programmed, and highly regulated process causing dramatic morphological and biochemical perturbations in the cellular machinery.Ganoderma lucidum is a basidiomycetes, polypore mushroom known for its pharmacological properties in cancer. The major bioconstituents inG. lucidum are terpenoid...
Source: Investigational New Drugs - October 28, 2017 Category: Drugs & Pharmacology Source Type: research

Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy – results of an exploratory phase I study
SummaryVinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 2...
Source: Investigational New Drugs - October 28, 2017 Category: Drugs & Pharmacology Source Type: research

Radiomics to predict immunotherapy-induced pneumonitis: proof of concept
This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 27, 2017 Category: Drugs & Pharmacology Source Type: research

Posterior reversible encephalopathy syndrome (PRES) induced by pazopanib, a multi-targeting tyrosine kinase inhibitor, in a patient with soft-tissue sarcoma: case report and review of the literature
We describe a case of a 49-year-old woman with retroperitoneal soft-tissue sarcoma who developed PRES during pazopanib administration. Pazopanib at 800  mg/day was administered as her third-line treatment at relapse. After 38 days of pazopanib, she was admitted to our hospital with severe headache, vomiting, and systemic hypertension. The next day, she developed consciousness deterioration and visual disturbance together with exacerbated systemic hypertension. Brain MR images revealed hyper-intense signals on FLAIR sequences in the bilateral occipital lobes and the left thalamus. Intravenous nicardipine injection...
Source: Investigational New Drugs - October 25, 2017 Category: Drugs & Pharmacology Source Type: research

Phase I study of the combination of crizotinib (as a MET inhibitor) and dasatinib (as a c-SRC inhibitor) in patients with advanced cancer
Conclusions The combination of crizotinib and dasatinib is safe to administer but tolerability is limited given the high rate of adverse events. Responses and durable stable disease were limited. Further precision therapy approach using this specific combination may be difficult given the toxicity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 19, 2017 Category: Drugs & Pharmacology Source Type: research

Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads
Conclusions Published ADC clinical data is limited by non-uniform reporting for toxicity and lack of dosing information, limiting the ability to develop quantitative models relating toxicity to exposure. However, the current analysis suggests that key G3/4 toxicities of ADCs in the clinic are likely off-target and related to payload. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 13, 2017 Category: Drugs & Pharmacology Source Type: research

Gastrointestinal perforation related to lenvatinib, an anti-angiogenic inhibitor that targets multiple receptor tyrosine kinases, in a patient with metastatic thyroid cancer
SummaryLenvatinib, a novel potent multikinase inhibitor, was approved for the treatment of radioiodine-refractory differentiated thyroid cancer based on results from phase III trial (SELECT study). Thyroid cancer is a diverse disease that includes anaplastic thyroid cancer (ATC), which the most aggressive form of the disease, although it accounts for
Source: Investigational New Drugs - October 11, 2017 Category: Drugs & Pharmacology Source Type: research

Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer: phase I results
SummaryPancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (
Source: Investigational New Drugs - October 9, 2017 Category: Drugs & Pharmacology Source Type: research

Hersintuzumab: A novel humanized anti-HER2 monoclonal antibody induces potent tumor growth inhibition
SummaryHumanized monoclonal antibodies (mAbs) against HER2 including trastuzumab and pertuzumab are widely used to treat HER2 overexpressing metastatic breast cancers. These two mAbs recognize distinct epitopes on HER2 and their combination induces a more potent blockade of HER2 signaling than trastuzumab alone. Recently, we have reported characterization of a new chimeric mAb (c-1T0) which binds to an epitope different from that recognized by trastuzumab and significantly inhibits proliferation of HER2 overexpressing tumor cells. Here, we describe humanization of this mAb by grafting all six complementarity determining re...
Source: Investigational New Drugs - October 6, 2017 Category: Drugs & Pharmacology Source Type: research

Phase I study of the combination of quinacrine and erlotinib in patients with locally advanced or metastatic non small cell lung cancer
Conclusion Combination of quinacrine and erlotinib was well tolerated but showed limited efficacy in advanced NSCLC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 2, 2017 Category: Drugs & Pharmacology Source Type: research

Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors
Conclusions Erdafitinib was well tolerated in Japanese patients with advanced or refractory solid tumors.Trial Registration: NCT01962532. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 30, 2017 Category: Drugs & Pharmacology Source Type: research

The kinesin Eg5 inhibitor K858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells
SummaryGlioblastoma multiforme is the most common primary malignant brain tumor and its current chemotherapeutic options are limited to temozolomide. Recently, some synthetic compounds acting as inhibitors of kinesin spindle protein Eg5 have shown pronounced antitumor activity. Our group has recently demonstrated that one of these kinesin Eg5 inhibitors, named K858, exerted important antiproliferative and apoptotic effects on breast cancer cells. Since glioblastoma cells usually express high levels of kinesin Eg5, we tested the effect of K858 on two human glioblastoma cell lines (U-251 and U-87) and found that K858 inhibit...
Source: Investigational New Drugs - September 30, 2017 Category: Drugs & Pharmacology Source Type: research

Association of Glutathione S-Transferase P-1 (GSTP-1) rs1695 polymorphism with overall survival in glioblastoma patients treated with combined radio-chemotherapy
SummaryGlioblastoma (GBM) is the most frequent malignant primary brain tumor in adults and, despite recent advances, the prognosis for this cancer remains dismal. The aims of this study were to test the influence ofXRCC1 rs25487,XRCC3 rs861539, XRCC3 rs1799794,RAD51 rs1801320 andGSTP-1 rs1695 single nucleotide polymorphisms on progression free survival (PFS) and overall survival (OS) in GBM patients treated with radiotherapy (RT) and temozolomide (TMZ). Fifty GBM patients treated with upfront radio-chemotherapy (RT 60  Gy/30 sessions; TMZ 75 mg/m2 during RT and 200  mg/m2 days 1 → 5 every...
Source: Investigational New Drugs - September 30, 2017 Category: Drugs & Pharmacology Source Type: research

Treatment-related serious adverse events and fatal adverse events with regorafenib in cancer patients: a meta-analysis of phase 3 randomized controlled trials
SummaryRegorafenib (Stivarga) is an oral small-molecule multikinase inhibitor commonly used against a variety of cancers. We performed a meta-analysis of all phase 3 randomized controlled trials (RCTs) of regorafenib to quantify the increased risk of SAEs and FAEs. We carried out a systematic search of electronic databases for studies published from inception to February 2017 without any restrictions. Eligibility criteria included phase 3 RCTs of tumors comparing regorafenib, alone or in combination with non-targeted chemotherapy (regorafenib arm) versus placebo or non-targeted chemotherapy (control arm). Data on SAEs and ...
Source: Investigational New Drugs - September 22, 2017 Category: Drugs & Pharmacology Source Type: research

Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial
Conclusion Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 22, 2017 Category: Drugs & Pharmacology Source Type: research

A phase I study to assess the mass balance, excretion, and pharmacokinetics of [ 14 C]-ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors
SummaryThis two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1  mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4  mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to asses...
Source: Investigational New Drugs - September 21, 2017 Category: Drugs & Pharmacology Source Type: research

Mechanisms of cancer cell killing by sea cucumber-derived compounds
SummaryThe aim of cancer therapy is to specifically eradicate tumor cells while causing minimal damage to normal tissues and minimal side-effects. Because of this, the use of natural substances with low toxicity is a good option. Sea cucumbers are one of many potential marine animals that contain valuable nutrients and medicinal properties. The medicinal value of sea cucumbers is attributed to the presence of bioactive agents with promising biological and pharmacological properties that include cytotoxic activity, induction of apoptosis, cell cycle arrest, inhibition of tumor growth, anti-metastatic and anti-angiogenic pro...
Source: Investigational New Drugs - September 18, 2017 Category: Drugs & Pharmacology Source Type: research

Novel inhibitors of lysine (K)-specific Demethylase 4A with anticancer activity
SummaryLysine (K)-specific demethylase 4A (KDM4A) is a histone demethylase that removes methyl residues from trimethylated or dimethylated histone 3 at lysines 9 and 36. Overexpression of KDM4A is found in various cancer types. To identify KDM4A inhibitors with anti-tumor functions, screening with an in vitro KDM4A enzyme activity assay was carried out. The benzylidenehydrazine analogue LDD2269 was selected, with an IC50 of 6.56  μM of KDM4A enzyme inhibition, and the binding mode was investigated using in silico molecular docking. Demethylation inhibition by LDD2269 was confirmed with a cell-based assay using anti...
Source: Investigational New Drugs - September 14, 2017 Category: Drugs & Pharmacology Source Type: research

Comparison of reporting phase I trial results in ClinicalTrials.gov and matched publications
SummaryBackground Data on completeness of reporting of phase I cancer clinical trials in publications are lacking.Methods TheClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching primary publications published prior to November 1, 2016. Reporting in primary publications was compared with theClinicalTrials.gov database using a 28-point score (2=complete; 1=partial; 0=no reporting) for 14 items related to study design, outcome measures and safety profile. Inconsistencies between primary publications andClinicalTrials.gov were recorded. Linea...
Source: Investigational New Drugs - September 14, 2017 Category: Drugs & Pharmacology Source Type: research

Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment
Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child –Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 11, 2017 Category: Drugs & Pharmacology Source Type: research

AN-7, a butyric acid prodrug, sensitizes cutaneous T-cell lymphoma cell lines to doxorubicin via inhibition of DNA double strand breaks repair
This study aimed to elucidate the mechanism underlying the effect of AN-7 on Dox-induced double-strand DNA breaks (DSBs) in CTCL, MyLa and Hut78 cell lines. The following markers/assays were employed: comet assay; western blot of γH2AX and p-KAP1; immunofluorescence of γH2AX nuclear foci; Western blot of repair protein; quantification of DSBs-repair through homologous recombination. DSB induction by Dox was evidenced by an increase in DSB markers, and DSBs-repair, by their subsequent decrease. The addition of AN-7 slightly increased Dox induction of DSBs in MyLa cells with no effect in Hut78 cells. AN-7 inhibit...
Source: Investigational New Drugs - September 8, 2017 Category: Drugs & Pharmacology Source Type: research

Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF V600 mutation-positive solid tumors: a phase 1 study
Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients withBRAF mutated malignant melanoma. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 7, 2017 Category: Drugs & Pharmacology Source Type: research

Crucial microRNAs and genes in metformin ’s anti-pancreatic cancer effect explored by microRNA-mRNA integrated analysis
SummaryDespite great improvements in surgical procedures and chemotherapy, pancreatic cancer remains one of the most aggressive and fatal human malignancies, with a low 5-year survival rate. Therefore, novel therapeutic strategies for the prevention and treatment of pancreatic cancer are urgently needed. The present study aimed to investigate the mechanisms by which metformin exerts its anticancer effects on the microRNA-mRNA interactions in human pancreatic cancer. Microarray and systematic analyses revealed that the anti-pancreatic cancer effects of metformin were correlated with 3 up-regulated microRNAs and 4 of their t...
Source: Investigational New Drugs - September 5, 2017 Category: Drugs & Pharmacology Source Type: research

Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies
Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300  mg/m2. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 4, 2017 Category: Drugs & Pharmacology Source Type: research

Phase II basket trial of perifosine monotherapy for recurrent gynecologic cancer with or without PIK3CA mutations
Conclusions Perifosine monotherapy showed good tolerability but expected efficacy was not achieved. Modest efficacy was demonstrated in ovarian cancer patients withPIK3CA mutations and endometrial cancer patients withPIK3CA wild-type; no difference was observed betweenPIK3CA wild-type and mutant in cervical cancer. Absence of PTEN expression may be predictive of clinical efficacy with perifosine monotherapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 2, 2017 Category: Drugs & Pharmacology Source Type: research

Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies
Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 30, 2017 Category: Drugs & Pharmacology Source Type: research

Vinblastine and antihelmintic mebendazole potentiate temozolomide in resistant gliomas
SummaryGlioblastoma (GBM) is a very aggressive tumor that has not had substantial therapeutic improvement since the introduction of temozolomide (TMZ) in combination with radiotherapy. Combining TMZ with other chemotherapeutic agents is a strategy that could be further explored for GBM. To search for molecular predictors of TMZ resistance, the TCGA (The Cancer Genome Atlas) database was utilized to assess the impact of specific genes on TMZ response. Patients whose tumors expressed low levels of FGFR3 and AKT2 responded poorly to TMZ. Combination treatment of vinblastine (VBL) plus mebendazole (MBZ) with TMZ was more effec...
Source: Investigational New Drugs - August 29, 2017 Category: Drugs & Pharmacology Source Type: research

Effect of alisertib, an investigational aurora a kinase inhibitor on the QTc interval in patients with advanced malignancies
SummaryAims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50  mg twice daily [BID] for 7 days in 21-day cycles).Methods Patients received a single dose of alisertib (50  mg) on Day 1, and multiple doses of alisertib (50 mg BID) on Days 4 through to the morning of Day 10 of the first cycle of treatment. Triplicate ECGs were collected at interva...
Source: Investigational New Drugs - August 18, 2017 Category: Drugs & Pharmacology Source Type: research

CUDC-907, a dual HDAC and PI3K inhibitor, reverses platinum drug resistance
SummaryPlatinum (Pt)-based anticancer drugs are the mainstay of treatment for solid cancers. However, resistance to Pt drugs develops rapidly, which can be caused by overexpression of multidrug resistance transporters and activation of DNA repair. CUDC-907 is a potent molecular targeted anticancer agent, rationally designed to simultaneously inhibit histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K). We investigated the potentiation effect of CUDC-907 on Pt drugs in resistant cancer cells. ABCC2 stably-transfected HEK293 cells and two pairs of parental and Pt-resistant cancer cell lines were used to test f...
Source: Investigational New Drugs - August 17, 2017 Category: Drugs & Pharmacology Source Type: research

First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile
Conclusions PU-H71 was well tolerated at the doses administered during this study (10 to 470  mg/m2/day), with no dose limiting toxicities. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 12, 2017 Category: Drugs & Pharmacology Source Type: research

Germline BRCA mutations in Asian patients with pancreatic adenocarcinoma: a prospective study evaluating risk category for genetic testing
Conclusion Personal or family history of breast or ovarian cancers is a feasible, cost-effective risk categorization for screening germlineBRCA mutations in Asian PDAC patients as 10% of this population had the pathogenic mutation herein. Future validation from a large, prospective cohort is needed. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 7, 2017 Category: Drugs & Pharmacology Source Type: research

Synthesis, characterization, and evaluation of Cd[L-proline] 2 , a novel histone deacetylase inhibitor that induces epigenetic modification of histone deacetylase isoforms in A549 cells
SummaryHistone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression through their effects on the compact chromatin structure. In clinical studies, several classes of histone deacetylase inhibitors (HDACi) have demonstrated potent anticancer activities with metal complexes. Hence, we synthesized cadmium –proline complexes using both the D- and L-isomers of proline and evaluated their biological activities by observing the efficiency of their inhibition of HDAC activity, ability to reduce the expression of HDAC isoforms in A549 cells and effect on apoptosis. The synthesized compou...
Source: Investigational New Drugs - August 3, 2017 Category: Drugs & Pharmacology Source Type: research

Addition of an antiangiogenic therapy, bevacizumab, to gemcitabine plus oxaliplatin improves survival in advanced biliary tract cancers
Conclusion In mBTC, the addition of bevacizumab to GEMOX increased the progression-free survival and was associated with manageable toxicity. These data pave the way for further evaluation of antiangiogenic agents in mBTC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 1, 2017 Category: Drugs & Pharmacology Source Type: research

A Phase I study to determine safety, pharmacokinetics, and pharmacodynamics of ANF-RHO ™, a novel PEGylated granulocyte colony-stimulating factor, in healthy volunteers
SummaryPatients receiving pegfilgrastim (Neulasta ®) for the treatment of neutropenia can experience bone pain following the injections required to achieve effective neutrophil levels. The safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of ANF-RHO™, a novel pegylated granulocyte colony stimulating factor, were assessed in a rando mized, controlled, double-blind Phase 1 clinical study in healthy volunteers. Subjects received a single subcutaneous dose of ANF-RHO over a range of 6 doses (5–50 μg/kg), placebo (saline), or the recommended clinical dose of pegfilgrastim administered at th...
Source: Investigational New Drugs - July 28, 2017 Category: Drugs & Pharmacology Source Type: research

Anti-invasive effects of CXCR4 and FAK inhibitors in non-small cell lung carcinomas with mutually inactivated p53 and PTEN tumor suppressors
In this study, we first examined the invasive characteristics of NSCLC cells with suppressed p53 and PTEN activity using wound healing, gelatin degradation and invasion assays. Further, changes in the expression of CXCR4 and FAK were evaluated by RT-qPCR and Western Blot analysis. Finally, we tested the ability of CXCR4 and FAK inhibitors (WZ811 and PF-573228, respectively) to suppress the migratory and invasive potential of p53/PTEN deficient NSCLC cells, in vitro and in vivo using metastatic models of human NSCLC. Our results showed that cells with mutually inactive p53 and PTEN have significantly increased invasive pote...
Source: Investigational New Drugs - July 22, 2017 Category: Drugs & Pharmacology Source Type: research

Induction of accelerated senescence by the microtubule-stabilizing agent peloruside A
SummaryChemotherapeutic agents can induce accelerated senescence in tumor cells, an irreversible state of cell cycle arrest. Paclitaxel, a microtubule-stabilizing agent used to treat solid tumors of the breast, ovary, and lung and discodermolide, another stabilizing agent from a marine sponge, induce senescence in cultured cancer cells. The aim of this study was to determine if the microtubule-stabilizing agent peloruside A, a polyketide natural product from a marine sponge, can induce accelerated senescence in a breast cancer cell line MCF7. Doxorubicin, a DNA-damaging agent, paclitaxel, and discodermolide were used as po...
Source: Investigational New Drugs - July 22, 2017 Category: Drugs & Pharmacology Source Type: research

Copper (II) complexes of bidentate ligands exhibit potent anti-cancer activity regardless of platinum sensitivity status
SummaryInsensitivity to platinum, either through inherent or acquired resistance, is a major clinical problem in the treatment of many solid tumors. Here, we explored the therapeutic potential of diethyldithiocarbamate (DDC), pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ), clioquinol (CQ) copper complexes in a panel of cancer cell lines that differ in their sensitivity to platins (cisplatin/carboplatin) using a high-content imaging system. Our data suggest that the copper complexes were effective against both platinum sensitive (IC50 ~ 1 μM platinum) and insensitive (IC50 >  5&...
Source: Investigational New Drugs - July 21, 2017 Category: Drugs & Pharmacology Source Type: research

Feasibility of olanzapine, multi acting receptor targeted antipsychotic agent, for the prevention of emesis caused by continuous cisplatin- or ifosfamide-based chemotherapy
Conclusion A 2.5  mg/day dosage of olanzapine is sufficient to prevent from CINV in Japanese patients receiving continuous five-day chemotherapy. A dose of 10 mg/day, which is recommended by international CINV guidelines, is also tolerated. If CINV is not controlled by an initial dose of 2.5 mg/day of olanzapine, dosage escalation is encouraged. Future studies should compare olanzapine with aprepitant. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 21, 2017 Category: Drugs & Pharmacology Source Type: research

Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors
Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 20, 2017 Category: Drugs & Pharmacology Source Type: research

Erratum to: A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors
(Source: Investigational New Drugs)
Source: Investigational New Drugs - July 5, 2017 Category: Drugs & Pharmacology Source Type: research

Safety and effectiveness of eribulin in Japanese patients with locally advanced or metastatic breast cancer: a post-marketing observational study
Conclusions The safety and effectiveness profile of eribulin was consistent with prior studies. Eribulin had a favorable risk-benefit balance when used in real-world clinical settings. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 29, 2017 Category: Drugs & Pharmacology Source Type: research

Chemotherapy-induced cardiomyopathy caused by Pemetrexed
We describe the case of a patient with advanced lung cancer and cardiomyopathy due to pemetrexed. A 59-year-old woman visited our hospital, and we found abnormal findings on a chest radiograph. She was diagnosed as having stage IV lung adenocarcinoma. Chemotherapy with cisplatin and pemetrexed every 3  weeks was initiated. After four cycles of chemotherapy, maintenance chemotherapy with pemetrexed was administered every 3 weeks. During the seventeenth cycle of pemetrexed, she had shortness of breath in her daily life. A chest radiograph showed an enlarged cardiothoracic ratio (66%), and the tra nsthoracic echocar...
Source: Investigational New Drugs - June 28, 2017 Category: Drugs & Pharmacology Source Type: research

Urolithins impair cell proliferation, arrest the cell cycle and induce apoptosis in UMUC3 bladder cancer cells
SummaryEllagitannins have been gaining attention as potential anticancer molecules. However, the low bioavailability of ellagitannins and their extensive metabolization in the gastrointestinal tract into ellagic acid and urolithins suggest that the health benefits of consuming ellagitannins rely on the direct effects of their metabolites. Recently, chemopreventive and chemotherapeutic activities were ascribed to urolithins. Nonetheless, there is still a need to screen and evaluate the selectivity of these molecules and to elucidate their cellular mechanisms of action. Therefore, this work focused on the antiproliferative e...
Source: Investigational New Drugs - June 20, 2017 Category: Drugs & Pharmacology Source Type: research

Decorin gene upregulation mediated by an adeno-associated virus vector increases intratumoral uptake of nab-paclitaxel in neuroblastoma via inhibition of stabilin-1
This study sought to investigate the effects of increased decorin (DCN) expression on the intratumoral uptake of nab-paclitaxel as a potential novel approach to NB. Correlation between the clinical characteristics of neuroblastoma and the expression of DCN, secreted protein acidic and rich in cysteine (SPARC) and stabilin-1 was evaluated. The anticancer effect of recombinant adeno-associated virus-DCN (rAAV-DCN) was assessed in vivo and in vitro. And the effect of rAAV-DCN on the intratumoral uptake of paclitaxel was also studied in neuroblastoma-grafted nude mice. Overall, 12.5%, 17.7%, and 71.9% of the tumors stained pos...
Source: Investigational New Drugs - June 20, 2017 Category: Drugs & Pharmacology Source Type: research

Phase II study of Amrubicin monotherapy in elderly or poor-risk patients with extensive disease of small cell lung cancer
Conclusions The results of the present study suggest that amrubicin could be considered as a viable treatment option for chemotherapy-naive elderly or poor-risk patients with ES-SCLC (Clinical trial registration number: UMIN000011055www.clinicaltrials.gov). (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 20, 2017 Category: Drugs & Pharmacology Source Type: research

A case of nivolumab-related cholangitis and literature review: how to look for the right tools for a correct diagnosis of this rare immune-related adverse event
SummaryAnti-programmed cell death-1 (PD-1) monoclonal antibodies, such as nivolumab, used for the treatment of several tumors, can trigger effector T-cells against tumor- and self-antigens, leading to the occurrence of different immune-related adverse events. Among them, liver injuries are rare and usually transient. To date, only four cases of immune-related cholangitis in non-small cell lung cancer (NSCLC) patients have been described during nivolumab treatment. Here, we describe laboratory tests, imaging and liver biopsy features that confirm this diagnosis as opposed to other forms of autoimmune liver disease; neverthe...
Source: Investigational New Drugs - June 20, 2017 Category: Drugs & Pharmacology Source Type: research

A phase Ib study of everolimus combined with metformin for patients with advanced cancer
Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 15, 2017 Category: Drugs & Pharmacology Source Type: research

Osimertinib reactivated immune-related colitis after treatment with anti-PD1 antibody for non-small cell lung cancer
We reported a case of relapsing immune-related colitis (initially caused by nivolumab) following osimertinib therapy for lung adenocarcinoma. A 45-year-old female who had never smoked was diagnosed with adenocarcinoma of the lung and underwent surgical resection. Four years after surgical resection, she was diagnosed with recurrent disease and was eventually treated with nivolumab as third-line therapy. One month after the completion of nivolumab therapy, the patient reported abdominal pain and frequent diarrhea. We diagnosed immune-related colitis and started oral prednisolone. However, the steroid therapy was ineffective...
Source: Investigational New Drugs - June 10, 2017 Category: Drugs & Pharmacology Source Type: research