Peloruside A, a microtubule-stabilizing agent, induces aneuploidy in ovarian cancer cells
Summary To ensure proper chromosome segregation, mitosis is tightly regulated by the spindle assembly checkpoint (SAC). Low concentrations of microtubule-stabilizing agents can induce aneuploid populations of cells in the absence of G2/M block, suggesting pertubation of the spindle checkpoint. We investigated the effects of peloruside A, a microtubule-stabilizing agent, on expression levels of several key cell cycle proteins, MAD2, BUBR1, p55CDC and cyclin B1. Synchronized 1A9 ovarian carcinoma cells were allowed to progress through the cell cycle in the presence or absence of peloruside A. Co-immunoprecipitation ...
Source: Investigational New Drugs - May 7, 2016 Category: Drugs & Pharmacology Source Type: research

Phase 1 study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases
Conclusion In a patient undergoing hepatectomy for CLM, 80 mg/m2 of S-1 and 130 mg/m2 of oxaliplatin are recommended as adjuvant therapy. A further study is required to confirm the efficacy and safety of this regimen on a larger scale. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 7, 2016 Category: Drugs & Pharmacology Source Type: research

Improved in vivo antitumor effect of a daunorubicin - GnRH-III bioconjugate modified by apoptosis inducing agent butyric acid on colorectal carcinoma bearing mice
Summary Compared to classical chemotherapy, peptide-based drug targeting is a promising therapeutic approach for cancer, which can provide increased selectivity and decreased side effects to anticancer drugs. Among various homing devices, gonadotropin-releasing hormone-III (GnRH-III) peptide represents a suitable targeting moiety, in particular in the treatment of hormone independent tumors that highly express GnRH receptors (e.g. colon carcinoma). We have previously shown that GnRH-III[4Lys(Ac),8Lys(Dau = Aoa)] bioconjugate, in which daunorubicin was attached via oxime linkage to the 8Lys of a GnRH-III ...
Source: Investigational New Drugs - May 5, 2016 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin
Summary GTx-024 (also known as enobosarm) is a first in class selective androgen receptor modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metab...
Source: Investigational New Drugs - April 22, 2016 Category: Drugs & Pharmacology Source Type: research

CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies
Abstract Expression of CD20 antigen by the most of transformed B cells is believed to be the driving force for targeting this molecule by using anti-CD20 monoclonal antibodies. While it is true that most lymphoma/leukemia patients can be cured, these regimens are limited by the emergence of treatment resistance. Based on these observations, development of anti-CD20 monoclonal antibodies and combination therapies have been recently proposed, in particular with the aim to optimize the cytotoxic activity. Here we outline a range of new experimental agents concerning the CD20 positive B-cell tumors which provide high ...
Source: Investigational New Drugs - April 13, 2016 Category: Drugs & Pharmacology Source Type: research

A Phase I study of olaparib and irinotecan in patients with colorectal cancer: Canadian Cancer Trials Group IND 187
Conclusions Olaparib can be combined with irinotecan if administered intermittently. Both olaparib and irinotecan required significant dose reductions. The lack of anti-tumor efficacy observed in this trial makes this combination of little interest for further clinical development. Trial Registration ID NCT00535353. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 13, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma
Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 8, 2016 Category: Drugs & Pharmacology Source Type: research

AZD9291 overcomes T790 M-mediated resistance through degradation of EGFR L858R/T790M in non-small cell lung cancer cells
Summary The discovery of activating mutations of epidermal growth factor receptor (EGFR) has resulted in the development of more effective treatments for non-small cell lung cancer (NSCLC). Although first-generation EGFR tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit, acquired resistance often occurs, most commonly (>50 %) via a T790 M resistance mutation. Although AZD9291 is selective for both T790 M and activating EGFR mutations over wild-type EGFR, it is highly active when T790 M is present, especially EGFRL858R/T790M, and modestly active when T790 M is a...
Source: Investigational New Drugs - April 5, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α 2 integrin inhibitor E7820 in patients with advanced solid tumors
Conclusions:Food had no effect on E7820 exposure. A dose of 50 mg BID was considered the MTD. Treatment with E7820 is safe and tolerable with 2/3 of patients (66.7 %) at MTD having SD as their best response. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 2, 2016 Category: Drugs & Pharmacology Source Type: research

Exposure–safety–efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study
Summary Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy...
Source: Investigational New Drugs - April 2, 2016 Category: Drugs & Pharmacology Source Type: research

Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison
The objective of the current study was to further elucidate the metabolic pathways of lenvatinib in humans and to compare these results to the metabolism in rats and monkeys. To this end, we used plasma, urine and feces collected in a human mass balance study after a single 24 mg (100 μCi) oral dose of 14C-lenvatinib. Metabolites of 14C-lenvatinib were identified using liquid chromatography (high resolution) mass spectrometry with off-line radioactivity detection. Close to 50 lenvatinib-related compounds were detected. In humans, unchanged lenvatinib accounted for 97 % of the radioactivity in plasma, and ...
Source: Investigational New Drugs - March 28, 2016 Category: Drugs & Pharmacology Source Type: research

Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors
Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 22, 2016 Category: Drugs & Pharmacology Source Type: research

Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer
Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 21, 2016 Category: Drugs & Pharmacology Source Type: research

The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells
Summary Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an a...
Source: Investigational New Drugs - March 19, 2016 Category: Drugs & Pharmacology Source Type: research

A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers
Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 18, 2016 Category: Drugs & Pharmacology Source Type: research

Molecular mode of action of NKP-1339 – a clinically investigated ruthenium-based drug – involves ER- and ROS-related effects in colon carcinoma cell lines
Abstract Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) is a clinically investigated ruthenium-based metal complex, which shows promising results in solid tumors, such as non-small cell lung cancer, colorectal carcinoma, and most distinctively in gastrointestinal neuroendocrine tumors. In previous studies, fast binding to albumin as well as transferrin could be shown. The enhanced permeability and retention (EPR) effect, which is diversely being exploited for tumor targeting, could therefore be applicable for NKP-1339. Here we studied the serum dependence of its biological activity in variou...
Source: Investigational New Drugs - March 18, 2016 Category: Drugs & Pharmacology Source Type: research

Peptide aptamer identified by molecular docking targeting translationally controlled tumor protein in leukemia cells
Summary Bioinformatics screening and molecular docking analyses were utilized to select high affinity peptides targeting translationally controlled tumor protein (TCTP). Selected peptide aptamers were tested towards cancer cell lines with different levels of TCTP expression. One peptide (WGQWPYHC) revealed specific cytotoxicity according to the TCTP expression in tumor cells without affecting normal cells. Western blot analysis showed peptide-induced down-regulation of TCTP as primary target as well as of cell-cycle related downstream proteins (CDK2, CDK6, Cyclin D3) in MOLT-4 leukemia cells. “WGQWPYHC&rdquo...
Source: Investigational New Drugs - March 14, 2016 Category: Drugs & Pharmacology Source Type: research

Microtubule-stabilizing properties of the avocado-derived toxins (+)-( R )-persin and (+)-( R )-tetrahydropersin in cancer cells and activity of related synthetic analogs
Summary The avocado toxin (+)-R-persin (persin) is active at low micromolar concentrations against breast cancer cells and synergizes with the estrogen receptor modulator 4-hydroxytamoxifen. Previous studies in the estrogen receptor-positive breast cancer cell line MCF-7 indicate that persin acts as a microtubule-stabilizing agent. In the present study, we further characterize the properties of persin and several new synthetic analogues in human ovarian cancer cells. Persin and tetrahydropersin cause G2M cell cycle arrest and increase intracellular microtubule polymerization. One analog (4-nitrophenyl)-deshydroxyp...
Source: Investigational New Drugs - March 12, 2016 Category: Drugs & Pharmacology Source Type: research

Why balls are not put inside the basket? A reflection on testicular cancer clinical trial design
Summary New concepts of trial design are being developed based on biomarkers, namely basket and umbrella trials. Basket trials appear optimally positioned to evaluate new molecular markers for testicular germ cell tumors, a rare heterogeneous disease with relatively few molecular alterations. However, not uncommonly, the “balls” fall outside the “basket”. In this short communication, we discussed the different causes limiting the inclusion of TGCT in basket trials and we proposed a new design for trials suitable for this malignancy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 10, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors
Conclusions The RP2D for IMGN901 of 60 mg/m2 administered for 3 consecutive days every 3 weeks was associated with an acceptable tolerability profile. Objective responses were observed in patients with advanced CD56+ cancers. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 9, 2016 Category: Drugs & Pharmacology Source Type: research

Convection-enhancement delivery of liposomal formulation of oxaliplatin shows less toxicity than oxaliplatin yet maintains a similar median survival time in F98 glioma-bearing rat model
In conclusion, a better tumoral accumulation was achieved when oxaliplatin and Lipoxal™ were injected by CED. The liposomal encapsulation of oxaliplatin reduced its toxic, while maintaining its antitumor potential. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 9, 2016 Category: Drugs & Pharmacology Source Type: research

A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors
Conclusions While generally low-grade, clinically relevant gastrointestinal toxicities occurred frequently with this oprozomib formulation. Despite dose-dependent increases in pharmacokinetics and pharmacodynamics, single-agent oprozomib had minimal antitumor activity in this patient population with advanced solid tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 29, 2016 Category: Drugs & Pharmacology Source Type: research

A multicenter phase 1/2a dose-escalation study of the antioxidant moiety of vitamin E 2,2,5,7,8-pentamethyl-6-chromanol (APC-100) in men with advanced prostate cancer
Conclusions APC-100 is a novel agent with dual mechanism of action functioning both as potent antioxidant as well as antiandrogen. No detectable APC-100 was found in the plasma at dose level 5 (2100 mg) and it was felt that maximal feasibility was nearly reached. APC-100 is being reformulated as a tablet to allow further dose escalation. Once a recommended phase 2 dose is established, future studies in prostate cancer chemoprevention should be conducted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 29, 2016 Category: Drugs & Pharmacology Source Type: research

Phase II study of amrubicin (SM-5887), a synthetic 9-aminoanthracycline, as first line treatment in patients with metastatic or unresectable soft tissue sarcoma: durable response in myxoid liposarcoma with TLS-CHOP translocation
Conclusions Amrubicin has efficacy comparable to doxorubicin in adult STS, is well tolerated and has no significant cardiac toxicity up to a cumulative dose of 4800 mg /m2. Topoisomerase II inhibition with amrubicin warrants further study as a potential ‘targeted therapy’ for TLS-CHOP-translocated myxoid liposarcoma. Results from this trial favor the use of amrubicin for the treatment of STS. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 20, 2016 Category: Drugs & Pharmacology Source Type: research

A never-smoker lung adenocarcinoma patient with a MET exon 14 mutation (D1028N) and a rapid partial response after crizotinib
We describe a case of clinical activity of crizotinib in a female patient with a lung adenocarcinoma displaying a MET exon 14 donor splice site mutation (D1028N) detected using next generation sequencing. Within 5 weeks of crizotinib therapy, a partial response was observed in this 67 year-old woman. Further clinical trials of crizotinib are needed for non-small cell lung cancer exhibiting MET mutations. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 18, 2016 Category: Drugs & Pharmacology Source Type: research

The novel pyrrolo-1,5-benzoxazepine, PBOX-15, synergistically enhances the apoptotic efficacy of imatinib in gastrointestinal stromal tumours; suggested mechanism of action of PBOX-15
In conclusion, our findings indicate the potential of PBOX-15 to improve the apoptotic response of IM in GIST cells and provide a more effective treatment option for GIST patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 17, 2016 Category: Drugs & Pharmacology Source Type: research

Targeted therapies in gastric cancer treatment: where we are and where we are going
Summary Gastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic se...
Source: Investigational New Drugs - February 12, 2016 Category: Drugs & Pharmacology Source Type: research

An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer
Summary Background Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A. Methods A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5 %, H1 ≥ 20 %, α = 10 % and β = 20 %). Eligibility included failure of at least one platinum-based regimen. Results F...
Source: Investigational New Drugs - February 12, 2016 Category: Drugs & Pharmacology Source Type: research

Two randomized, double-blind, placebo-controlled, dose-escalation phase 1 studies evaluating BTH1677, a 1, 3–1,6 beta glucan pathogen associated molecular pattern, in healthy volunteer subjects
Conclusions BTH1677 was well tolerated after single doses up to 6 mg/kg and after 7 daily doses up to 4 mg/kg. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 11, 2016 Category: Drugs & Pharmacology Source Type: research

Successful human epidermal growth receptor 2-targeted therapy beyond disease progression for extramammary Paget’s disease
Summary Extramammary Paget’s disease is a malignant intraepithelial carcinoma, which constitutes less than 1 % of all vulvar malignancies. Surgical resection is the first treatment of choice and standard chemotherapy has not been established for advanced or recurrent disease. Experimental and clinical studies have identified human epidermal growth receptor 2 as a potential therapeutic target. A 63-year-old male was referred for recurrent extramammary Paget’s disease after surgery. Human epidermal growth receptor 2 was shown to be overexpressed and amplified by immunohistochemical analysis and fluo...
Source: Investigational New Drugs - February 9, 2016 Category: Drugs & Pharmacology Source Type: research

A phase II study of cediranib, an oral VEGF inhibitor, in previously untreated patients with metastatic or recurrent malignant melanoma
Conclusions Although 2 patients had stable disease at 6 months, the short median time to progression and lack of any objective responses indicate that single agent cediranib at this dose and schedule is not sufficiently active to warrant study continuation. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 3, 2016 Category: Drugs & Pharmacology Source Type: research

RRx-001, A novel dinitroazetidine radiosensitizer
Summary The ‘holy grail’ in radiation oncology is to improve the outcome of radiation therapy (RT) with a radiosensitizer—a systemic chemical/biochemical agent that additively or synergistically sensitizes tumor cells to radiation in the absence of significant toxicity. Similar to the oxygen effect, in which DNA bases modified by reactive oxygen species prevent repair of the cellular radiation damage, these compounds in general magnify free radical formation, leading to the permanent “fixation” of the resultant chemical change in the DNA structure. The purpose of this review is to pre...
Source: Investigational New Drugs - February 3, 2016 Category: Drugs & Pharmacology Source Type: research

A dose escalating phase I study of GLPG0187, a broad spectrum integrin receptor antagonist, in adult patients with progressive high-grade glioma and other advanced solid malignancies
Conclusions GLPG0187 was well tolerated with a dose-proportional PK profile upon continuous infusion. No formal maximal tolerated dose could be established. GLPG0187 showed signs of target engagement with a favourable toxicity profile. However, continuous infusion of GLPG0187 failed to show signs of monotherapy efficacy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 20, 2016 Category: Drugs & Pharmacology Source Type: research

Cytotoxic effects of natural and semisynthetic cucurbitacins on lung cancer cell line A549
The objective of this work was to evaluate four cucurbitacins (CUCs) for their cytotoxic activity, effects on apoptosis induction, cell cycle progression, anti-migratory, and anti-invasive effects on the human NSCLC cell line (A549 cells). Our findings showed that these CUCs could suppress human NSCLC cell growth in vitro through their effects on the PI3Kinase and MAPK pathways, which lead to programmed cell death induction, as well as inhibition of cell migration and cell invasion. Additionally, these effects culminate in apoptosis induction and G2/M cell cycle arrest by modulating cyclin B1 expression, and in the mitigat...
Source: Investigational New Drugs - January 16, 2016 Category: Drugs & Pharmacology Source Type: research

Effect of regulation reform on clinical trials for registering novel therapeutic agents in Taiwan: a chronological analysis
Summary The registration process for new drugs is crucial in the clinical application of medicines. Previously, the registration of imported novel therapeutic agents in Taiwan depended considerably on their approvals in developed countries. The Taiwanese government enacted Article 38–1 of the Regulations for Registration of Medicinal Products in September 2009. According to the new submission criteria, approvals may be exempted if the number of Taiwanese participants in the clinical trials fulfills the required threshold. The present study compared the profiles of clinical trials of novel therapeutic agents ...
Source: Investigational New Drugs - January 16, 2016 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics, metabolism, and excretion of 14 C-labeled belinostat in patients with recurrent or progressive malignancies
Conclusion Mass balance was achieved (~95 % mean recovery), with metabolism identified as the primary route of elimination. Radioactivity was predominantly excreted renally as belinostat metabolites. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 14, 2016 Category: Drugs & Pharmacology Source Type: research

Post-progression survival in patients with advanced hepatocellular carcinoma resistant to sorafenib
Conclusions Child–Pugh score of ≥7, AFP of>400 ng/mL, MVI, and new extrahepatic lesions at the time of progression may be utilized to assess the prognosis and taken into consideration when designing second-line trials. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 14, 2016 Category: Drugs & Pharmacology Source Type: research

Targeting BRAF mutants in clear-cell sarcomas of soft tissue: beyond sarcoma or melanoma classification
(Source: Investigational New Drugs)
Source: Investigational New Drugs - January 8, 2016 Category: Drugs & Pharmacology Source Type: research

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats
This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague–Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pum...
Source: Investigational New Drugs - January 4, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I trial of vandetanib in combination with gemcitabine and capecitabine in patients with advanced solid tumors with an expanded cohort in pancreatic and biliary cancers
Conclusion The combination of gemcitabine, capecitabine and vandetanib is well tolerated at the recommended phase II dose of gemcitabine 1000 mg/m2 weekly for three consecutive weeks, capecitabine 850 mg/m2 BID days 1–21, and vandetanib 300 mg daily, every 28 days. This combination demonstrated promising activity in pancreaticobiliary cancers and further evaluation is warranted in these diseases. NCT00551096. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 30, 2015 Category: Drugs & Pharmacology Source Type: research

Effect of CH-35, a novel anti-tumor colchicine analogue, on breast cancer cells overexpressing the βIII isotype of tubulin
Summary The subunit protein of microtubules is tubulin, which has been the target for some of the most successful and widely used anti-tumor drugs. Most of the drugs that target tubulin bind to the β subunit. There are many isotypes of β-tubulin and their distributions differ among different tissues. The βIII isotype is over-expressed in many tumors, particularly those that are aggressive, metastatic, and drug resistant. We have previously reported the design and synthesis of a series of compounds to fit the colchicine site on βIII but not on the other isotypes. In the current study, we tested ...
Source: Investigational New Drugs - December 21, 2015 Category: Drugs & Pharmacology Source Type: research

A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)
Conclusions The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 19, 2015 Category: Drugs & Pharmacology Source Type: research

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer
Conclusions The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 14, 2015 Category: Drugs & Pharmacology Source Type: research

Acknowledgement of Reviewers 2015
(Source: Investigational New Drugs)
Source: Investigational New Drugs - December 11, 2015 Category: Drugs & Pharmacology Source Type: research

Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo®) after intravenous administration in Non-human primates
Conclusions In three animals, each serving as their own control, we demonstrate that the pharmacokinetic profile of VSLI shows markedly prolonged clearance (approximately 400-fold lower) of total vincristine in comparison to the standard aqueous formulation, enhancing our understanding of VSLI pharmacokinetics. Several clinical trials incorporating VSLI as substitution for standard vincristine are in progress. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 10, 2015 Category: Drugs & Pharmacology Source Type: research

Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as first-line treatment of advanced HER2-positive gastric cancer: a multicenter phase II study
Conclusions B-DOCT is a safe and active combination in HER2-positive GC, supporting further investigations of DOC with HER2/vascular endothelial growth factor (VEGF) inhibition in HER2-positive GC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 8, 2015 Category: Drugs & Pharmacology Source Type: research

Phase I, dose-escalating study of elisidepsin (Irvalec ® ), a plasma membrane-disrupting marine antitumor agent, in combination with erlotinib in patients with advanced malignant solid tumors
Conclusion The difficulty in combining elisidepsin with the standard dose of erlotinib (150 mg), together with the lack of antitumor activity, made the combination unattractive for further development. The trial was closed without having determined a recommended dose. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 2, 2015 Category: Drugs & Pharmacology Source Type: research

Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with advanced solid tumors
Conclusions Volasertib had a manageable safety profile up to the MTD determined as 300 mg. Exposure to volasertib and its metabolite increased with increasing doses. The safety profile of volasertib in Japanese patients is comparable with those previously obtained in Caucasian patients. These data support enrollment of Japanese patients in global clinical trials without dose modification. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 2, 2015 Category: Drugs & Pharmacology Source Type: research

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors
Conclusions MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 1, 2015 Category: Drugs & Pharmacology Source Type: research

LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models
We report the preclinical therapeutic activity of LY2603618 (CHK1 inhibitor) at inhibiting CHK1 activation by gemcitabine and enhancing in vivo efficacy. The in vivo biochemical effects of CHK1 inhibition in the absence or presence of DNA damage were measured in human tumor xenograft models. Colon, lung and pancreatic xenografts models were treated with gemcitabine, LY2603618, or gemcitabine plus LY2603618. Gemcitabine treatment alone induced a significant increase in CHK1 autophosphorylation over untreated tumors. Co-administration of LY2603618 with gemcitabine showed a clear inhibition of CHK1 autophosphorylation for at ...
Source: Investigational New Drugs - November 27, 2015 Category: Drugs & Pharmacology Source Type: research