Predictive factors of renal toxicities related to anti-VEGFR multikinase inhibitors in phase 1 trials
Conclusions A majority of the DLTs associated with AMKI in phase 1 trials are renal toxicities. Baseline hypertension and stage 3 CKD (NKF-KDOQI) might help to better identify patients at risk of AMKI-related renal toxicities. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 24, 2016 Category: Drugs & Pharmacology Source Type: research

A photodynamic bifunctional conjugate for prostate cancer: an in vitro mechanistic study
SummaryPhotodynamic therapy (PDT) has drawn considerable attention for its efficacy against certain types of cancers. It shows however limits in the case of deep cancers, favoring tumor recurrence under suboptimal conditions. More insight into the molecular mechanisms of PDT-induced cytotoxicity and cytoprotection is essential to extend and strengthen this therapeutic modality. As PDT induces iNOS/NO in both tumor and microenvironment, we examined the role of nitric oxide (NO) in cytotoxicity and cytoprotection. Our findings show that NO mediates its cellular effects by acting on the NF- κB/YY1/RKIP loop, which contr...
Source: Investigational New Drugs - October 10, 2016 Category: Drugs & Pharmacology Source Type: research

4-methylumbelliferone and imatinib combination enhances senescence induction in chronic myeloid leukemia cell lines
SummaryChronic myeloid leukemia (CML) is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome which encodes a constitutively activated tyrosine kinase (BCR-ABL). The first line treatment for CML consists onBCR-ABL inhibitors such as Imatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, it is of great value to find molecules that enhance the anti-proliferative effect of first-line drugs. Hyaluronan is the main glycosaminglican of the extracellular matrix which is involved in tumor progression and multidrug resistance. We have previously demonstr...
Source: Investigational New Drugs - October 7, 2016 Category: Drugs & Pharmacology Source Type: research

Evaluating the role of phase I expansion cohorts in oncologic drug development
SummaryImportance Use of expansion cohorts (EC) in phase I trials is increasing. However, the utility of phase I EC in aiding drug development is unclear. We sought to determine factors associated with the inclusion of EC in phase I studies and the impact of EC on subsequent clinical development.Methods We performed a systematic review of all phase I trials published in theJournal of Clinical Oncology between June 2004 and May 2014. Presence of an EC, number of participants, funding source, class of agent, tumor type, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) were identified. Subsequent conduct of ph...
Source: Investigational New Drugs - October 6, 2016 Category: Drugs & Pharmacology Source Type: research

Incidence of infusion reactions to anti-neoplastic agents in early phase clinical trials: The MD Anderson Cancer Center experience
AbstractInfusion reactions (IRs) to anti-neoplastic agents require prompt recognition and immediate treatment to avert significant complications. We conducted a retrospective review of the medical records of consecutive patients who received anti-neoplastic therapy in the outpatient treatment center of the Department of Investigational Cancer Therapeutics from January 1, 2013 to November 30, 2013. Of the 597 patients who received treatment, 9 (1.5  %) had IRs (all ≤ grade 2). The most common IRs observed on first occurrence were chills (n = 5), itching, rash, and facial flushing (n = 3 each). Th...
Source: Investigational New Drugs - September 28, 2016 Category: Drugs & Pharmacology Source Type: research

Propolis extracts from the northern region of Thailand suppress cancer cell growth through induction of apoptosis pathways
SummaryThe continual increase in mortality rates and number of cancer cases is a matter of serious concern in developing countries. The incorporation of natural products into classical cancer treatment approaches is a promising direction. The mechanisms of A549 and HeLa cancer cell death induction by ethanolic extracts of propolis samples from Phayao, Chiang Mai, and Nan provinces in northern Thailand were investigated in this study. The propolis extract from Chiang Mai showed the highest antioxidant activity and the greatest total phenolic content. The propolis extract from Nan also exhibited the highest total flavonoid c...
Source: Investigational New Drugs - September 20, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors
Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 20, 2016 Category: Drugs & Pharmacology Source Type: research

New water-soluble palladium(II) complexes of lidocaine and phenylcyanamide derivative ligands: cytotoxicity and cellular response mechanisms
SummaryThree new palladium(II) complexes of lidocaine and phenylcyanamide derivative ligands of formula K[Pd(2,6-Me2pcyd)2(LC)],1, K[Pd(2,6-Et2pcyd)2(LC)],2, K[Pd(2,6-Cl2pcyd)2(LC)],3 (LC: lidocaine, 2,6-Me2pcyd: 2,6-dimethyl phenylcyanamide, 2,6-Et2pcyd: 2,6-diethyl phenylcyanamide, 2,6-Cl2pcyd: 2,6-dichloro phenylcyanamide) have been synthesized and fully characterized. The complexes1–3 revealed a significant in vitro antiproliferative activity against human ovarian carcinoma (A2780), colorectal adenocarcinoma (HT29), breast (MCF-7), liver hepatocellular carcinoma (HepG-2) and lung adenocarcinoma (A549) cancer cell...
Source: Investigational New Drugs - September 18, 2016 Category: Drugs & Pharmacology Source Type: research

A retrospective analysis of 14 consecutive Chinese patients with unresectable or metastatic alveolar soft part sarcoma treated with sunitinib
Conclusions Sunitinib is effective in locally unresectable or metastatic ASPS with a good safety profile. Neoadjuvant treatment with sunitinib improves the chance of resection for patients with locally advanced ASPS. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 7, 2016 Category: Drugs & Pharmacology Source Type: research

Osimertinib-induced interstitial lung disease after treatment with anti-PD1 antibody
We report a case of a 38-year-old woman who was diagnosed with stage IV lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790  M mutation on exon 20. The patient was treated with osimertinib, a third-generationEGFR tyrosine kinase inhibitor (EGFR-TKI) following treatment with nivolumab, an anti-Programmed Cell Death 1 (anti-PD1) antibody. After initiating osimertinib treatment, the patient began to complain of low-grade fever and shortness of breath without hypoxemia, and her chest radiograph and a CT scan revealed a remarkable antitumor response, although faint...
Source: Investigational New Drugs - September 5, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I study of NK105, a nanomicellar paclitaxel formulation, administered on a weekly schedule in patients with solid tumors
AbstractPrevious studies have established the rationale for NK105, a nanomicellar formulation of paclitaxel, administered every 3  weeks. The aim of this phase I study was to determine the recommended dose and pharmacokinetics of weekly administered NK105. NK105 was administered by a 30-min infusion once weekly for three consecutive weeks in each 4-week cycle. In the dose-escalation phase, three to seven patients with solid tumors were enrolled to each of the four dose levels (50–100 mg/m2;n = 16). At a dose level of 100 mg/m2, predefined dose-limiting toxicity (DLT) manifested in only o...
Source: Investigational New Drugs - September 4, 2016 Category: Drugs & Pharmacology Source Type: research

Involvement of AMP-activated protein kinase in mediating pyrrolo-1,5-benzoxazepine –induced apoptosis in neuroblastoma cells
This study provides new insights into understanding the molecular and cellular mechanisms involved in PBOX-induced cell death in neuroblastoma and further support s their future use as novel anti-cancer agents for the treatment of neuroblastoma. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 1, 2016 Category: Drugs & Pharmacology Source Type: research

The novel kinase inhibitor ponatinib is an effective anti-angiogenic agent against neuroblastoma
Conclusions Ponatinib reduces neuroblastoma cell viabilityin vitro and reduces tumor growth and vascularityin vivo. The antitumor effects of ponatinib suggest its potential as a novel therapeutic agent for neuroblastoma, and further preclinical testing is warranted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 31, 2016 Category: Drugs & Pharmacology Source Type: research

Comparative effects of doxorubicin and a doxorubicin analog, 13-deoxy, 5-iminodoxorubicin (GPX-150), on human topoisomerase II β activity and cardiac function in a chronic rabbit model
Conclusions Unlike DOX, DIDOX did not cause chronic cardiotoxicity and did not appear to interact with topoisomerase II β in decatenation assays consistent with the hypothesis that inhibition of the topoisomerase IIβ/DNA reaction may be a contributor of the mechanism of chronic DOX cardiotoxicity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 30, 2016 Category: Drugs & Pharmacology Source Type: research

Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer
In conclusion, pictilisib was shown to have good safety and tolerability in Japanese patients with advanced solid tumors. A recommended dose of pictilisib in monotherapy was determined to be 340 mg once daily. For combination with CP + BEV, tolerability up to 260 mg/day was confirmed. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 26, 2016 Category: Drugs & Pharmacology Source Type: research

Sunitinib maintenance therapy after response to docetaxel in metastatic castration resistant prostate cancer (mCRPC)
Conclusion Sunitinib was tolerable as maintenance therapy but median PFS was significantly lower than the predefined threshold of 6  months. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 25, 2016 Category: Drugs & Pharmacology Source Type: research

Adding checkpoint inhibitors to tyrosine kinase inhibitors targeting EGFR/ALK in non-small cell lung cancer: a new therapeutic strategy
SummaryAfter the massive approval of checkpoint inhibitors in the treatment of numerous malignancies and settings, checkpoint inhibitors-based combination therapies are emerging as a new therapeutic modality. Nivolumab and pembrolizumab (anti-PD1 agents) were recently approved as second-line treatment in NSCLC after progression on platinum-doublets. In parallel, targeting EGFR/ALK in NSCLC using tyrosine kinase inhibitors (TKI) demonstrated remarkable outcomes and was approved as standard treatment, in patients with EGFR mutation or ALK rearrangement. Combining TKI targeting EGFR/ALK with checkpoint inhibitors seems a prom...
Source: Investigational New Drugs - August 24, 2016 Category: Drugs & Pharmacology Source Type: research

Clinical, pharmacodynamic and pharmacokinetic results of a prospective phase II study on oral metronomic vinorelbine and dexamethasone in castration-resistant prostate cancer patients
SummaryThe aim of the present study was to evaluate clinical activity, and the pharmacodynamic and pharmacokinetic profiles, of oral metronomic vinorelbine (VNR) plus dexamethasone (DEX) in metastatic castration-resistant prostate cancer (mCRPC) patients. Fourty-one patients (92  % chemotherapy-resistant) received 30 mg/day VNR p.o. thrice a week plus 1 mg/day DEX p.o. until disease progression. Plasma soluble B cell antigen 7 homolog 3 (sB7-H3), vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1), were measured by ELISA. Plasma VNR was detected using a LC-MS-MS system. The fraction of pa...
Source: Investigational New Drugs - August 23, 2016 Category: Drugs & Pharmacology Source Type: research

Successful treatment with afatinib after gefitinib- and erlotinib-induced hepatotoxicity
SummaryClinical trials of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have shown that some patients receiving these agents develop severe hepatotoxicity that necessitates treatment cessation. Both drugs undergo extensive hepatic metabolism mediated predominantly by cytochrome P450 family enzymes. Afatinib is a second-generation, irreversible EGFR-TKI that competes with ATP for binding to EGFR and the related proteins HER2 and HER4 and whose major circulating metabolites are covalent drug-protein adducts. We here describe a patient withEGFR mutation –positive l...
Source: Investigational New Drugs - August 22, 2016 Category: Drugs & Pharmacology Source Type: research

Comprehensive analysis of clinical development and regulatory submission promotion schemes for oncologic drugs as the Japanese national projects
We examined all oncologic drugs for adult patients approved or discussed through these schemes, for the first time. All the data are publicly available. In total, 197 applications/demands (181 indications and 16 dosages/uses) were collected. As of December 31, 2015, 64 indications and 10 dosages/uses were approved as off-label drugs through these schemes without conducting additional registration trials in Japan. Furthermore, 46 indications and two dosages/uses were approved after registration trials in Japan requested by the national scheme councils. Regarding the following 23 indications of the 197 applications/demands, ...
Source: Investigational New Drugs - August 18, 2016 Category: Drugs & Pharmacology Source Type: research

Treatment outcome of PD-1 immune checkpoint inhibitor in Asian metastatic melanoma patients: correlative analysis with PD-L1 immunohistochemistry
Conclusions The treatment outcome to PD-1 antibody was not different in acral/mucosal melanoma when compared with cutaneous melanoma. The immunohistochemical PD-L1 expression seemed to be correlated with better clinical outcomes of anti-PD-1 treatment in limited cases. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 3, 2016 Category: Drugs & Pharmacology Source Type: research

Sunitinib - induced sudden hearing loss
(Source: Investigational New Drugs)
Source: Investigational New Drugs - July 29, 2016 Category: Drugs & Pharmacology Source Type: research

Molecular and cellular effects of a novel hydroxamate-based HDAC inhibitor – belinostat – in glioblastoma cell lines: a preliminary report
Summary Histone deacetylase (HDAC) inhibitors are now intensively investigated as potential cytostatic agents in many malignancies. Here, we provide novel information concerning the influence of belinostat (Bel), a hydroxamate-based pan-HDAC inhibitor, on glioblastoma LN-229 and LN-18 cells. We found that LN-229 cells stimulated with 2  μmol/L of Bel for 48 h resulted in 70 % apoptosis, while equivalent treatment of LN-18 cells resulted in only 28 % apoptosis. In LN-229 cells this effect was followed by up-regulation of pro-apoptotic genes including Puma , Bim , Chop and p21 . In treated LN-18 cell...
Source: Investigational New Drugs - July 28, 2016 Category: Drugs & Pharmacology Source Type: research

The renal effects of ALK inhibitors
Summary Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. In clinical practice, three small molecule inhibitors of ALK-1 are used, namely crizotinib, ceritinib and alectinib. Several more agents are in active pre-clinical and clinical studies. Crizotinib is approved for the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). According to the package insert and published literature, treatment with crizotinib appears to be associated with kidney failure as well as an increased risk for the development and progression of renal cysts. In addition, this agent is...
Source: Investigational New Drugs - July 28, 2016 Category: Drugs & Pharmacology Source Type: research

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors
Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 22, 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 ( & gt;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 EGFR L858R/T790M , and modestly active when T790  M is...
Source: Investigational New Drugs - July 21, 2016 Category: Drugs & Pharmacology Source Type: research

Continuation maintenance therapy with S-1 in chemotherapy-na ïve patients with advanced squamous cell lung cancer
Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 21, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer
Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 20, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies
Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 16, 2016 Category: Drugs & Pharmacology Source Type: research

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors
Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAFV600E mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 15, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I trial of the aurora kinase inhibitor , ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia
Summary ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase, as well as c-Kit, FLT3 and VEGFR2. A phase I study was conducted to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and toxicities of ENMD-2076 in patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Patients received escalating doses of ENMD-2076 administered orally daily [225 mg (n = 7), 375 mg (n = 6), 325 mg (n = 9), or 275 mg (n = 5)]. Twenty-seven patients were treated (26 AML; 1 CMML-2). The most common n...
Source: Investigational New Drugs - July 11, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors
Conclusions Atezolizumab was well tolerated in Japanese patients at doses up to 20 mg/kg q3w. The safety profile and Cycle 1 serum atezolizumab concentrations were similar to those previously observed in non-Japanese patients. These data support the participation of Japanese patients in ongoing pivotal global studies of atezolizumab. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 30, 2016 Category: Drugs & Pharmacology Source Type: research

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer
Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 26, 2016 Category: Drugs & Pharmacology Source Type: research

Intravenous and intraperitoneal paclitaxel with S-1 for treatment of refractory pancreatic cancer with malignant ascites
Conclusion Combination chemotherapy consisting of intravenous and intraperitoneal PTX with S-1 showed acceptable toxicity and favorable efficacy in pancreatic cancer patients with malignant ascites. (Clinical trial registration number: UMIN000005306) (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 22, 2016 Category: Drugs & Pharmacology Source Type: research

Involvement of AMP-activated protein kinase in mediating pyrrolo-1,5-benzoxazepine–induced apoptosis in neuroblastoma cells
This study provides new insights into understanding the molecular and cellular mechanisms involved in PBOX-induced cell death in neuroblastoma and further supports their future use as novel anti-cancer agents for the treatment of neuroblastoma. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 21, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I trial of dacomitinib, a pan-human epidermal growth factor receptor (HER) inhibitor, with concurrent radiotherapy and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (XDC-001)
Conclusions The triple combination has a tolerable side effect profile and dose levels 15 mg and 30 mg were cleared safely. The addition of dacomitinib did not preclude delivery of standard chemoradiotherapy. Studies testing the addition of other HER-targeted therapies to platinum-based concurrent chemo-radiotherapy in LA-SCCHN have failed to demonstrate improved patient outcomes and have reported trends towards excessive toxicities. These results generated uncertainty regarding the future of these agents in combination with chemo-radiation for the treatment of LA-SCCHN, which ultimately led to the early terminat...
Source: Investigational New Drugs - June 10, 2016 Category: Drugs & Pharmacology Source Type: research

Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer
Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 8, 2016 Category: Drugs & Pharmacology Source Type: research

Intravitreal vascular endothelial growth factor (VEGF) inhibitor injection in unrecognised early pregnancy
Summary The use of intravitreal vascular endothelial growth factor (VEGF) inhibitor medications has widened considerably to include indications affecting females of reproductive age. Our patient was inadvertently exposed to bevacizumab within the first trimester when placental growth and fetal organogenesis take place and patient suffered pregnancy loss. There is insufficient information to suggest that such use is safe, nor is there definitive evidence to suggest that it causes harm. We advise that ophthalmologists discuss pregnancy with women of childbearing age undergoing intraocular anti-VEGF injections and in...
Source: Investigational New Drugs - June 1, 2016 Category: Drugs & Pharmacology Source Type: research

A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer
Conclusion: Although met with a favorable toxicity profile, the addition of AT-101 to docetaxel in R/M HNSCC does not appear to demonstrate evidence of efficacy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 25, 2016 Category: Drugs & Pharmacology Source Type: research

Prediction of response to everolimus in neuroendocrine tumors: evaluation of clinical, biological and histological factors
Summary Objectives Several targeted therapies are available for metastatic neuroendocrine tumours (NETs) but no predictive factor of response to these treatments has been identified yet. Our aim was to identify and evaluate clinical, biological, histological and functional markers of response to everolimus. Methods We retrospectively reviewed 53 patients with NETs treated with everolimus (68 % in clinical trials). Clinical, biological and histological data were analyzed. The functional marker p-p70S6K, a main effector of the mTOR pathway, was studied by immunohistochemistry in 43 cases. Prognos...
Source: Investigational New Drugs - May 25, 2016 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and excretion of 14 C-omacetaxine in patients with advanced solid tumors
Summary Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of 14C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m2 14C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168&...
Source: Investigational New Drugs - May 24, 2016 Category: Drugs & Pharmacology Source Type: research

The imidazoline compound RX871024 promotes insulinoma cell death independent of AMP-activated protein kinase inhibition
Summary We have previously shown that the insulinotropic imidazoline compound RX871024 induces death of insulinoma MIN6 cells, an effect involving stimulation of c-Jun N-terminal kinase (JNK) and caspase 3. It has also been reported that AMP-activated protein kinase (AMPK) activates JNK and induces β-cell death. Here we show that RX871024, but not another insulinotropic imidazoline compound (BL11282), suppressed AMPK activity in MIN6 cells. The inhibitory effect of RX871024 on AMPK was supported by the observation that the imidazoline induced lipid droplet formation in the cytoplasm of MIN6 cells. This reflec...
Source: Investigational New Drugs - May 24, 2016 Category: Drugs & Pharmacology Source Type: research

In vitro and in vivo antineoplastic and immunological effects of pterocarpanquinone LQB-118
In this report we describe its antineoplastic effect in vivo and assess its toxicity toward the immune system. Treated mice presented no changes in weight of primary and secondary organs of the immune system nor their cellular composition. Immunophenotyping showed that treatment increased CD4+ thymocytes and proportionally reduced the CD4+CD8+ subpopulation in the thymus. No significant changes were observed in T CD8+ peripheral lymphocytes nor was the activation of fresh T cells affected after treatment. LQB-118 induced apoptosis in murine tumor cells in vitro, being synergistic with the autophagy promoter rapamycin. Furt...
Source: Investigational New Drugs - May 17, 2016 Category: Drugs & Pharmacology Source Type: research

The aurora kinase inhibitor VX-680 shows anti-cancer effects in primary metastatic cells and the SW13 cell line
Abstract New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies. Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells)...
Source: Investigational New Drugs - May 13, 2016 Category: Drugs & Pharmacology Source Type: research

Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer
Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 9, 2016 Category: Drugs & Pharmacology Source Type: research

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 6, 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 6, 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 4, 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 21, 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 12, 2016 Category: Drugs & Pharmacology Source Type: research