The old CEACAMs find their new role in tumor immunotherapy
SummaryCarcinoembryonic antigen-related cell adhesion molecules (CEACAMs) contain 12 family members(CEACAM1 、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEACAM7、CEACAM8、CEACAM16、CEACAM18、CEACAM19、CEACAM20 and CEACAM21)and are expressed diversely in different normal and tumor tissues. CEA (CEACAM5) has been used as a tumor biomarker since 1965. Here we review the latest research and development of the structures, expression, and function of CEACAMs in normal and tumor tissues, and their application in the tumor diagnosis, prognosis, and treatment. We focus on recent clinical studies of CEA targeted cancer immunother...
Source: Investigational New Drugs - June 2, 2020 Category: Drugs & Pharmacology Source Type: research

A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer
SummaryVantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3  + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 wee...
Source: Investigational New Drugs - May 10, 2020 Category: Drugs & Pharmacology Source Type: research

Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma
Conclusions In patients with P53WT advanced solid tumors or MM, AMG 232 showed acceptable safety and dose-proportional pharmacokinetics, and stable disease was observed. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 10, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic characteristics of vactosertib, a new activin receptor-like kinase 5 inhibitor, in patients with advanced solid tumors in a first-in-human phase 1 study
Conclusions Vactosertib pharmacokinetics were dose-proportional within tested dose range with negligible accumulation when administered once daily for five days. Considering the short half-life, it seems necessary to administer vactosertib twice- or thrice-daily to maintain its concentrations above minimum effective level over a dosing interval. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 10, 2020 Category: Drugs & Pharmacology Source Type: research

A pilot study on intermittent every other days of 5-dose Filgrastim compared with single Pegfilgrastim in breast Cancer patients receiving adjuvant Docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy
Conclusion We observed no significant differences between the two methods of prophylaxis in terms of FN and G3/4 neutropenia incidence in patients receiving adjuvant TAC chemotherapy. Intermittent every other days 5-dose filgrastim may be available alternative to pegfilgrastim. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 10, 2020 Category: Drugs & Pharmacology Source Type: research

Modernizing adverse events analysis in oncology clinical trials using alternative approaches: rationale and design of the MOTIVATE trial
SummaryIn oncology clinical research, the analysis and reporting of adverse events is of major interest. A consistent depiction of the safety profile of a new treatment is as crucial in establishing how to use it as its antitumor activity. The advent of new therapeutics has led to major changes in the management of patients and targeted therapies or immune checkpoint inhibitors are administered continuously for months or even years. However, the classical methods of adverse events analysis are no longer adequate to properly assess their safety profile. Indeed, the worst grade method and time-to-event analysis cannot captur...
Source: Investigational New Drugs - May 7, 2020 Category: Drugs & Pharmacology Source Type: research

Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low C max and improved tolerability, in patients with solid tumors
Summary5-fluorouracil (5-FU) and 5-FU derivatives, such as capecitabine, UFT, and S-1, are the mainstay of chemotherapy treatment for gastrointestinal cancers, and other solid tumors. Compared with other cytotoxic chemotherapies, these drugs generally have a favorable safety profile, but hematologic and gastrointestinal toxicities remain common. DFP-11207 is a novel oral cytotoxic agent that combines a 5-FU pro-drug with a reversible DPD inhibitor and a potent inhibitor of OPRT, resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicities. In this Phase I study (NCT...
Source: Investigational New Drugs - May 6, 2020 Category: Drugs & Pharmacology Source Type: research

CPBMF65, a synthetic human uridine phosphorylase-1 inhibitor, reduces HepG2 cell proliferation through cell cycle arrest and senescence
In conclusion, results show, for the first time, the ability of a hUP1 inhibitor (CPBMF65) to reduce HepG2 cell proliferation through cell cycle arrest and senescence. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 4, 2020 Category: Drugs & Pharmacology Source Type: research

The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells
SummaryOne of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptos...
Source: Investigational New Drugs - May 4, 2020 Category: Drugs & Pharmacology Source Type: research

Apatinib, a novel VEGFR-2 tyrosine kinase inhibitor, for relapsed and refractory nasopharyngeal carcinoma: data from an open-label, single-arm, exploratory study
SummaryPurpose Apatinib, a new tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has shown promising efficacy against several solid cancers, but evidence of its efficacy against relapsed and refractory nasopharyngeal carcinoma is limited. We investigated the efficacy and safety of apatinib for relapsed and refractory nasopharyngeal carcinoma in an open-label, single-arm, phase II clinical trial. Fifty-one patients with relapsed and refractory nasopharyngeal carcinoma in the First Affiliated Hospital, Zhengzhou University, who met the inclusion criteria were enrolled in the study. All patien...
Source: Investigational New Drugs - May 3, 2020 Category: Drugs & Pharmacology Source Type: research

Tivantinib inhibits the VEGF signaling pathway and induces apoptosis in gastric cancer cells with c-MET or VEGFA amplification
In this study, we evaluated the effects of tivantinib on the suppression of gastric cancer (GC) cell migration and apoptosis. We also examined the mechanism of action of tivantinib by oncogenic pathway analysis. We applied an RNA-sequencing approach in 34 GC patients to identify oncogenes that are differentially expressed in GC tissues. To examine the inhibitory effect of tivantinib on GC cells, we conducted apoptosis analysis using an annexin V-APC/PI apoptosis detection kit and trans-well migration assay with human GC cell lines. For oncogenic pathway analysis, Western blot and quantitative real-time PCR analysis were us...
Source: Investigational New Drugs - May 2, 2020 Category: Drugs & Pharmacology Source Type: research

The near-infrared fluorescent dye IR-780 was coupled with cabazitaxel for castration-resistant prostate cancer imaging and therapy
SummaryA new drug, Caba-780, was synthesized by chemical coupling of the heptamethyl phthalocyanine near-infrared fluorescent (NIRF) dye IR-780 and the paclitaxel-based chemotherapeutic drug cabazitaxel. Then, the potential value of Caba-780 in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) was evaluated. The CRPC cell lines DU145 and PC-3, as well as the normal human prostate stromal cell line WPMY-1, were used to evaluate the uptake of Caba-780 and its antitumor effect in vitro. The distribution, antitumor effect, and safety of Caba-780 were also evaluated in tumor-bearing mouse xenograft mode...
Source: Investigational New Drugs - May 2, 2020 Category: Drugs & Pharmacology Source Type: research

A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors
Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 24, 2020 Category: Drugs & Pharmacology Source Type: research

Targeting c-Met in triple negative breast cancer: preclinical studies using the c-Met inhibitor, Cpd A
Conclusions Despite Cpd A having a potential role in reducing cancer cell metastasis, identification of strong predictive biomarkers of c-Met sensitivity would be essential to the development of a c-Met targeted treatment for an appropriately selected cohort of TNBC patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 22, 2020 Category: Drugs & Pharmacology Source Type: research

Quantification of the pharmacokinetic-toxicodynamic relationship of oral docetaxel co-administered with ritonavir
Conclusions A PK-TOX model was successfully developed. This model can be used to evaluate the probability of developing a DLT following treatment with oral docetaxel and ritonavir in different dosing regimens. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 19, 2020 Category: Drugs & Pharmacology Source Type: research

Structure-based design, synthesis, and evaluation of the biological activity of novel phosphoroorganic small molecule IAP antagonists
SummaryOne of the strategies employed by novel anticancer therapies is to put the process of apoptosis back on track by blocking the interaction between inhibitor of apoptosis proteins (IAPs) and caspases. The activity of caspases is modulated by the caspases themselves in a caspase/procaspase proteolytic cascade and by their interaction with IAPs. Caspases can be released from the inhibitory influence of IAPs by proapoptotic proteins such as secondary mitochondrial activator of caspases (Smac) that share an IAP binding motif (IBM). The main purpose of the present study was the design and synthesis of phosphorus-based pept...
Source: Investigational New Drugs - April 8, 2020 Category: Drugs & Pharmacology Source Type: research

Phase 1 dose escalation trial of TAS-102 (trifluridine/tipiracil) and temozolomide in the treatment of advanced neuroendocrine tumors
This study evaluated the safety of TAS-102 in combination with TMZ in patients in neuroendocrine tumors. Escalating doses of TMZ (100, 150 and 200  mg/m2) on days 8 –12 were given in combination with TAS-102 (35 mg/m2 twice a day) on days 1 –5 and 8–12 of a 28 day cycle in subjects with advanced NETs. Primary endpoints were safety and determination of maximum tolerated dose (MTD). Growth factor support was mandated starting with level 2 to avoid treatment delays. Fifteen evaluable subjects were enrolled in the phase 1 study. No d ose limiting toxicities (DLTs) were observed on level 1....
Source: Investigational New Drugs - April 6, 2020 Category: Drugs & Pharmacology Source Type: research

Dasatinib-induced chylothorax: report of a case and review of the literature
SummaryDasatinib is a tyrosine kinase inhibitor for the treatment of BCR-ABL-positive chronic myeloid leukaemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL). Although fluid retention is a common adverse event associated with dasatinib, chylothorax is exceptionally rare. The pathological mechanism, clinical manifestation and management of dasatinib-induced chylothorax are completely unclear. A 71-year-old man treated with dasatinib for CML was admitted for progressive dyspnea. Computed tomography (CT) showed a pleural effusion that was more prominent on the right thoracic cavity. Thoracentes...
Source: Investigational New Drugs - April 4, 2020 Category: Drugs & Pharmacology Source Type: research

A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer
Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS.Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 3, 2020 Category: Drugs & Pharmacology Source Type: research

A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer
SummaryPurpose SM-88 (D,L-alpha-metyrosine; racemetyrosine) is a novel anti-cancer agent, used with melanin, phenytoin, and sirolimus (SMK Therapy). This pilot first-in-human study characterized the safety, tolerability, and efficacy of SMK Therapy in subjects with advanced metastatic cancer.Methods All subjects (n = 30) received SMK Therapy for an initial 6 week Cycle (5 days on, 2 off per week) and continued if well tolerated. Safety signals, clinical response, overall survival, progression free survival (PFS), and quality of life changes were assessed.Results The most common drug related adv...
Source: Investigational New Drugs - March 11, 2020 Category: Drugs & Pharmacology Source Type: research

Phase 1 study to evaluate safety, tolerability and pharmacokinetics of a novel intra-tympanic administered thiosulfate to prevent cisplatin-induced hearing loss in cancer patients
This study has demonstrated that intratympanic administration of DB-020 results in nominal systemic increases in thiosulfate levels, hence it should not compromise cisplatin anti-tumor efficacy. Furthermore, DB-020 was safe and well tolerated with most adverse events reported as transient, of mild-to-moderate severity and related to the IT administration procedure. These results support the desig n and execution of the ongoing proof-of-concept study, DB-020-002, to assess otoprotection using DB-020 in cancer patients receiving cisplatin without negatively impacting cisplatin anti-tumor efficacy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 10, 2020 Category: Drugs & Pharmacology Source Type: research

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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