A truncated apoptin protein variant selectively kills cancer cells
SummaryApoptin is a nonstructural protein encoded by one of the three open reading frames of the chicken anemia virus genome. It has attracted a great deal of interest due to its ability to induce apoptosis in multiple transformed and malignant mammalian cell lines without affecting primary and non-transformed cells. However, the use of Apoptin as an anticancer drug is restricted by its strong tendency to aggregate. A number of methods to overcome this problem have been proposed, including transduction techniques to deliver the Apoptin gene into tumor cells, but all such methods have certain drawbacks. Here we describe tha...
Source: Investigational New Drugs - January 24, 2017 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and excretion of 14 C –Plitidepsin in patients with advanced cancer
This study shows that red blood cells are a major distribution compartment and that the biliary route is the main route of total radioactivity excretion. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 23, 2017 Category: Drugs & Pharmacology Source Type: research

A phase 1 study of the pharmacokinetics of nucleoside analog trifluridine and thymidine phosphorylase inhibitor tipiracil (components of TAS-102) vs trifluridine alone
Conclusion Tipiracil administered in combination with trifluridine significantly increased exposure to trifluridine compared with trifluridine alone. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 23, 2017 Category: Drugs & Pharmacology Source Type: research

Phase I study of lurbinectedin, a synthetic tetrahydroisoquinoline that inhibits activated transcription, induces DNA single- and double-strand breaks, on a weekly × 2 every-3-week schedule
Conclusion The recommended phase II dose of lurbinectedin is 5  mg, administered as a 1-h infusion on days 1 and 8 every 3 weeks. These data support further testing of this dose and schedule, particularly in soft tissue sarcoma. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 20, 2017 Category: Drugs & Pharmacology Source Type: research

A phase I and pharmacokinetic study of afilbercept with FOLFIRI: comparison of Chinese and Caucasian populations
Conclusion For Chinese patients with pre-treated advanced solid malignancies, 4  mg/kg of aflibercept in combination with FOLFIRI was well-tolerated, demonstrated preliminary anti-tumor activity and had a PK profile consistent with that in Caucasian patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 19, 2017 Category: Drugs & Pharmacology Source Type: research

Risks and benefits of phase I liver dysfunction studies: should patients with severe liver dysfunction be included in these trials?
Conclusion Given poor survival of patients with liver dysfunction, we need better criteria, such as albumin levels, for optimally selecting patients for liver dysfunction studies. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 19, 2017 Category: Drugs & Pharmacology Source Type: research

Acknowledgement of Reviewers 2016
(Source: Investigational New Drugs)
Source: Investigational New Drugs - January 14, 2017 Category: Drugs & Pharmacology Source Type: research

Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study
Conclusions AZD4547 was well tolerated in Japanese patients, with best response of stable disease ≥4 weeks. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 10, 2017 Category: Drugs & Pharmacology Source Type: research

First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors
Conclusions The MTD and recommended phase II dose were determined to be 4.34  mg/kg. Ocular toxicities accounted for the DLTs observed, as previously reported with monomethylauristatin-F payloads. Further studies are warranted to investigate clinical activity of this agent in patients with 5T4-expressing tumors.Trial registration ID: NCT01891669 (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 9, 2017 Category: Drugs & Pharmacology Source Type: research

Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice
SummaryThe sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60  mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC0 →∞, 31% and 27% lower liver and kidney AUC0 →∞ and 2.2-fold higher AUC0 →∞ in brain (allp 
Source: Investigational New Drugs - January 9, 2017 Category: Drugs & Pharmacology Source Type: research

Zebrafish phenotypic screen identifies novel notch antagonists
SummaryZebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293T ΔE) identifie...
Source: Investigational New Drugs - January 5, 2017 Category: Drugs & Pharmacology Source Type: research

A first-in-human Phase 1 study of epirubicin-conjugated polymer micelles (K-912/NC-6300) in patients with advanced or recurrent solid tumors
Conclusions This study showed that K-912 was well tolerated in patients with various solid tumors and exhibited less toxicity than conventional epirubicin formulations. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 4, 2017 Category: Drugs & Pharmacology Source Type: research

First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors
Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure. This agent could be studied further in combination with other agents, pending further proof-of-target-engagement. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 3, 2017 Category: Drugs & Pharmacology Source Type: research

Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth
SummaryTranscription factor Specificity protein  1 (Sp1) and its downstream target survivin (inhibitor of apoptosis protein), play major roles in the pathogenesis of various cancers. Ewing Sarcoma (ES) is a common soft tissue/bone tumor in adolescent and young adults. Overexpression of survivin is also linked to the aggressiveness and poor prog nosis of ES. Small molecule Tolfenamic acid (TA) inhibits Sp1 and survivin in cancer cells. In this investigation, we demonstrate a strategy to target Sp1 and survivin using TA and positive control Mithramycin A (Mit) to inhibit ES cell growth. Knock down of Sp1 using smal...
Source: Investigational New Drugs - December 26, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I study of tivantinib in combination with temsirolimus in patients with advanced solid tumors
Conclusions The combination of tivantinib with temsirolimus appears to be well tolerated with evidence of clinical activity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 21, 2016 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species
SummaryIsobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable ant...
Source: Investigational New Drugs - December 14, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors
Conclusions Nivolumab at doses of 1 –20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 8, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors
Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110  mg/m2 for non-HCC and 93  mg/m2 for HCC patients. Additional dose schedules of MRX34 have been explored to improve tolerability. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 5, 2016 Category: Drugs & Pharmacology Source Type: research

Current achievements and future perspectives of metronomic chemotherapy
SummaryIn recent years, many anticancer drugs have been tested at metronomic dosages for a variety of tumours. Mechanisms of action attributed to metronomic chemotherapy (MCT) include antiangiogenesis, immunomodulation, direct inhibition of tumour growth, effect on tumour initiating cells and the modulation of clonal evolution. An active clinical research, aimed at testing MCT in several cancers, has been conducted over the past 15  years. However, because the majority of available results come from earlier phase II studies, mainly performed in the area of breast cancer (BC), it is clear that there are areas still to ...
Source: Investigational New Drugs - December 1, 2016 Category: Drugs & Pharmacology Source Type: research

Erratum to: The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma
(Source: Investigational New Drugs)
Source: Investigational New Drugs - November 29, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors
Conclusions The RD for this combination is PM01183 3.0  mg FD (or 1.6 mg/m2)/gemcitabine 800  mg/m2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 21, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I trial investigating pulsatile erlotinib in combination with gemcitabine and oxaliplatin in advanced biliary tract cancers
SummaryAdvanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy. The purpose of this study was to assess the safety of pulsatile erlotinib with GEMOX. This was a single-institution phase Ib study ...
Source: Investigational New Drugs - November 16, 2016 Category: Drugs & Pharmacology Source Type: research

A phase 1 study combining the HER3 antibody seribantumab (MM-121) and cetuximab with and without irinotecan
Conclusions Seribantumab/cetuximab was well tolerated and patients experienced toxicities typical to EGFR inhibition. Unlike the seribantumab/cetuximab doublet, seribantumab/cetuximab/irinotecan was difficult to tolerate in this heavily pretreated population. There was limited efficacy of the combination therapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 16, 2016 Category: Drugs & Pharmacology Source Type: research

Safety of raltegravir-based antiretroviral therapy in HIV-infected patients receiving multi-kinase inhibitors
Conclusions The present data represent the first documentation of the concomitant use of raltegravir-containing HAART and MKIs in HIV-infected adult patients with advanced non-AIDS defining malignancies, with a reassuring safety profile. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 12, 2016 Category: Drugs & Pharmacology Source Type: research

Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer
Conclusions Orteronel 400  mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 8, 2016 Category: Drugs & Pharmacology Source Type: research

Alofanib, an allosteric FGFR2 inhibitor, has potent effects on ovarian cancer growth in preclinical studies
SummayPurpose Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. We investigated antitumor activity of alofanib (RPT835), a novel allosteric FGFR2 inhibitor, in ovarian cancer in vitro and in vivo.Methods Equal amounts of ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1 –3 protein expression using Wes. To assess the efficacy of alofanib on FGF-mediated cell proliferation, SKOV3 cells were incubated and were treated with serially diluted alofanib. Basic FGF was added at a concentr...
Source: Investigational New Drugs - November 3, 2016 Category: Drugs & Pharmacology Source Type: research

Erlotinib pharmacokinetics: a critical parameter influencing acute toxicity in elderly patients over 75  years-old
Conclusion The risk of overexposure to erlotinib increases with age. Reduced lean body mass may explain erlotinib pharmacokinetics and excessive acute toxicity in the elderly. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 29, 2016 Category: Drugs & Pharmacology Source Type: research

The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma
SummaryMedulloblastoma (MB) is the most common solid tumor among pediatric patients and corresponds to 20  % of all pediatric intracranial tumors in this age group. Its treatment currently involves significant side effects. Epigenetic changes such as DNA methylation may contribute to its development and progression. DNA methyltransferase (DNMT) inhibitors have shown promising anticancer effects. The ag ent Zebularine acts as an inhibitor of DNA methylation and shows low toxicity and high efficacy, being a promising adjuvant agent for anti-cancer chemotherapy. Several studies have reported its effects on different type...
Source: Investigational New Drugs - October 26, 2016 Category: Drugs & Pharmacology Source Type: research

Targeting the protein ubiquitination machinery in melanoma by the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924)
AbstractBackground The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma.Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, ...
Source: Investigational New Drugs - October 25, 2016 Category: Drugs & Pharmacology Source Type: research

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 25, 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 11, 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 8, 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 7, 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 29, 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 21, 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 21, 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 19, 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 8, 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 6, 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 5, 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 - September 1, 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 31, 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 27, 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 26, 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 25, 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 24, 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 23, 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 19, 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 4, 2016 Category: Drugs & Pharmacology Source Type: research