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The Lancet. Gastroenterology &... Jan 2018Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial... (Randomized Controlled Trial)
Randomized Controlled Trial
Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.
BACKGROUND
Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial chemoembolisation (cTACE) in patients with unresectable hepatocellular carcinoma.
METHODS
This randomised, double-blind, placebo-controlled, phase 3 study was done at 75 sites in Japan, South Korea, and Taiwan. Patients with unresectable hepatocellular carcinoma, no extra-hepatic tumour spread, and Child-Pugh score of 6 or less were randomly assigned (1:1) by interactive web response system using a computer-generated sequence to receive orantinib or placebo, within 28 days of cTACE. Randomisation was stratified by region, Child-Pugh score (5 vs 6), alpha fetoprotein concentrations (<400 ng/mL vs ≥400 ng/mL), and size of the largest lesion (≤50 mm vs >50 mm). Orantinib at 200 mg, twice per day, or placebo was given orally until TACE failure or unacceptable toxicity. The patients, investigators, and study personnel were masked to treatment assignment. The primary endpoint was overall survival, analysed in the full analysis set (patients who had received at least one dose of study drug). This study is registered at ClinicalTrials.gov, number NCT01465464, and has been terminated.
FINDINGS
Between Dec 10, 2010, and Nov 21, 2013, 889 patients were randomly assigned to receive either orantinib (445 patients; 444 treated) or placebo (444 patients; all treated). The study was ended at interim analysis for futility evaluation. Median follow-up was 17·3 months (IQR 11·3-26·4). There was no improvement in overall survival with orantinib compared with placebo (median 31·1 months [95% CI 26·5-34·5] vs 32·3 months [28·4-not reached]; hazard ratio 1·090, 95% CI 0·878-1·352; p=0·435). The main adverse events in the orantinib group were oedema, ascites, and elevation of aspartate and alanine aminotransferases. The most frequent adverse events of grade 3 or worse in the orantinib group included elevated aspartate aminotransferase (189 [43%] patients in the oratinib group, 161 [36%] patients in the placebo group), elevated alanine aminotransferase (150 [34%] patients in the oratinib group, 132 (30%) patients in the placebo group), and hypertension (47 [11%] patients in the oratinib group, 39 [9%] patients in the placebo group). Serious adverse events were reported in 200 (45%) patients in the orantinib group and 134 (30%) patients in the placebo group.
INTERPRETATION
Orantinib combined with cTACE did not improve overall survival in patients with unresectable hepatocellular carcinoma.
FUNDING
Taiho Pharmaceutical.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Double-Blind Method; Early Termination of Clinical Trials; Female; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Oxindoles; Propionates; Protein Kinase Inhibitors; Pyrroles; Survival Analysis; Treatment Outcome
PubMed: 28988687
DOI: 10.1016/S2468-1253(17)30290-X -
Medical Oncology (Northwood, London,... May 2019A randomized, phase III trial of orantinib in combination with transcatheter arterial chemoembolization (TACE) did not prolong overall survival (OS) over placebo...
A randomized, phase III trial of orantinib in combination with transcatheter arterial chemoembolization (TACE) did not prolong overall survival (OS) over placebo (ORIENTAL study). A subgroup analysis was conducted to evaluate the efficacy and safety of orantinib in Japanese patients enrolled in the ORIENTAL study. The data of Japanese patients from this study were analyzed. The overall survival (OS), time to progression (TTP), and time to TACE failure (TTTF) were compared between orantinib and placebo arms using stratified log-rank test. Since TTTF in patients with Barcelona Clinic Liver Cancer stage B (BCLC-B) showed favor outcome in this study, the OS and TTTF according to BCLC staging system were also analyzed. The subgroup analysis consisted of 219 and 213 patients in the orantinib and placebo arms. Median OS was 32.5 vs 33.0 months (p = 0.906), median TTP was 4.7 vs 3.1 months (p = 0.011), and median TTTF was 25.3 vs 18.2 months (p = 0.160) in the orantinib and placebo groups, respectively. Patients with BCLC-B in the orantinib and placebo groups showed a median OS of 33.7 and 30.1 months, respectively (p = 0.260), while the corresponding median TTTF were 25.3 and 14.0 months (p = 0.125). The Japanese population safety profile was similar to all over population in the ORIENTAL study. No significant differences were observed in the OS and TTTF though the TTP was significantly improved in the orantinib arm. The OS and TTTF showed a tendency to be prolonged following orantinib treatment of Japanese HCC patients with BCLC-B in the ORIENTAL study.
Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Female; Humans; Indoles; Japan; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Oxindoles; Propionates; Protein Kinase Inhibitors; Pyrroles; Survival Rate; Treatment Outcome
PubMed: 31053989
DOI: 10.1007/s12032-019-1272-2 -
Toxicology and Applied Pharmacology Jun 2022Capillary pericytes have numerous functions important for tissue maintenance. Changes in pericyte function are implicated in diseases such as cancer, where...
Capillary pericytes have numerous functions important for tissue maintenance. Changes in pericyte function are implicated in diseases such as cancer, where pericyte-mediated angiogenesis contributes to the blood supply that tumors use to survive. Some anti-cancer agents, like imatinib, target platelet-derived growth factor receptor-beta (PDGFRβ). Healthy pericytes rely on PDGFRβ phosphorylation for their survival. Therefore, we hypothesised that pharmacological agents that block PDGFRβ phosphorylation could be used to kill pericytes. We treated human brain vascular pericytes, which express PDGFRβ, with three receptor tyrosine kinase inhibitors: imatinib, sunitinib and orantinib. Imatinib and sunitinib, but not orantinib, inhibited PDGFRβ phosphorylation in pericytes. Imatinib and sunitinib also reduced viability, prevented proliferation, and induced death, while orantinib only blocked pericyte proliferation. Overall, we found that receptor tyrosine kinase inhibitors that block PDGFRβ phosphorylation cause healthy pericytes to die in vitro. While useful in cancer to limit tumor growth, these agents could impair healthy brain pericyte survival and impact brain function.
Topics: Brain; Humans; Imatinib Mesylate; Neoplasms; Pericytes; Protein Kinase Inhibitors; Receptor, Platelet-Derived Growth Factor beta; Sunitinib
PubMed: 35443205
DOI: 10.1016/j.taap.2022.116025 -
Cancer Research and Treatment Oct 2017Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer... (Review)
Review
Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer growth and metastasis, and recent studies indicate that pharmacologic blockade of angiogenesis is a promising approach to therapy. In this systematic review, we summarize current literature on the clinical benefit of anti-angiogenic agents in advanced gastric cancer. We conducted a systematic search of PubMed and conference proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies aimed to prospectively evaluate the efficacy and safety of anti-angiogenic agents in advanced gastric or gastroesophageal junction cancer. Each trial investigated at least one of the following endpoints: overall survival, progression-free survival/time to progression, and/or objective response rate. Our search yielded 139 publications. Forty-two met the predefined inclusion criteria. Included studies reported outcomes with apatinib, axitinib, bevacizumab, orantinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, telatinib, and vandetanib. Second-line therapy with ramucirumab and third-line therapy with apatinib are the only anti-angiogenic agents so far shown to significantly improve survival of patients with advanced gastric cancer. Overall, agents that specifically target the vascular endothelial growth factor ligand or receptor have better safety profile compared to multi-target tyrosine kinase inhibitors.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Clinical Trials as Topic; Esophageal Neoplasms; Esophagogastric Junction; Humans; Molecular Targeted Therapy; Neoplasm Staging; Protein Kinase Inhibitors; Quality of Life; Receptor, ErbB-2; Stomach Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 28052652
DOI: 10.4143/crt.2016.176 -
Pharmaceutics Apr 2021Since coronavirus disease 2019 (COVID-19) is a serious new worldwide public health crisis with significant morbidity and mortality, effective therapeutic treatments are...
Since coronavirus disease 2019 (COVID-19) is a serious new worldwide public health crisis with significant morbidity and mortality, effective therapeutic treatments are urgently needed. Drug repurposing is an efficient and cost-effective strategy with minimum risk for identifying novel potential treatment options by repositioning therapies that were previously approved for other clinical outcomes. Here, we used an integrated network-based pharmacologic and transcriptomic approach to screen drug candidates novel for COVID-19 treatment. Network-based proximity scores were calculated to identify the drug-disease pharmacological effect between drug-target relationship modules and COVID-19 related genes. Gene set enrichment analysis (GSEA) was then performed to determine whether drug candidates influence the expression of COVID-19 related genes and examine the sensitivity of the repurposing drug treatment to peripheral immune cell types. Moreover, we used the complementary exposure model to recommend potential synergistic drug combinations. We identified 18 individual drug candidates including nicardipine, orantinib, tipifarnib and promethazine which have not previously been proposed as possible treatments for COVID-19. Additionally, 30 synergistic drug pairs were ultimately recommended including fostamatinib plus tretinoin and orantinib plus valproic acid. Differential expression genes of most repurposing drugs were enriched significantly in B cells. The findings may potentially accelerate the discovery and establishment of an effective therapeutic treatment plan for COVID-19 patients.
PubMed: 33919660
DOI: 10.3390/pharmaceutics13040545 -
Hepatology Research : the Official... Oct 2015Hepatocellular carcinoma (HCC) can be lethal due to its aggressive course and lack of effective systemic therapies for advanced disease. Sorafenib is the only systemic... (Review)
Review
Hepatocellular carcinoma (HCC) can be lethal due to its aggressive course and lack of effective systemic therapies for advanced disease. Sorafenib is the only systemic therapy that has demonstrated an overall survival benefit in patients with advanced HCC, and new agents for treatment of advanced HCC are needed. The multiple pathways involved in HCC oncogenesis, proliferation and survival provide many opportunities for the development of molecularly targeted therapies. Molecular targets of interest have expanded from angiogenesis to cancer cell-directed oncogenic signaling pathways for treatment of advanced HCC. Agents targeting vascular endothelial growth factor receptor, epidermal growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-mesenchymal-epithelial transition factor-1 and mammalian target of rapamycin signaling have been actively explored. This article focuses on the evaluation of molecular agents targeting pathogenic HCC and provides a review of recently completed phase III drug studies (e.g. involving sorafenib, sunitinib, brivanib, linifanib, erlotinib, everolimus, ramucirumab or orantinib) and ongoing drug studies (e.g. involving lenvatinib, regorafenib, tivantinib or cabozantinib) of molecularly targeted agents in advanced HCC, including a brief description of the biologic rationale behind these agents.
PubMed: 25472913
DOI: 10.1111/hepr.12459 -
Current Opinion in Investigational... Aug 2001SUGEN is developing SU-6668, a tyrosine kinase inhibitor that inhibits three distinct growth factor receptor targets, for the potential treatment of cancer [304530]. The... (Review)
Review
SUGEN is developing SU-6668, a tyrosine kinase inhibitor that inhibits three distinct growth factor receptor targets, for the potential treatment of cancer [304530]. The compound is in phase I trials in the UK and US [321260], [374505]. A report in January 2001 stated that phase I/II trials for hematological and solid tumors were expected to commence shortly thereafter [395657]. In May 2001, phase I data from a dose-escalation study conducted at UCLA were presented at the 37th ASCO meeting in San Francisco, CA. By that time, 74 patients had been enrolled in this study which aimed to determine the toxicities of SU-6668 when delivered to fed and fasting patients. SU-6668 was administered orally either once or twice-daily at doses of 100 to 2400 mg/m2 to patients diagnosed as having advanced malignancies. Accrual in phase I is continuing to define the toxicities of doses > 200 mg/m2 twice-daily [409984], [411418]. In December 1998, SUGEN filed an IND with the FDA for the clinical testing of this compound with oral and iv formulations [310237]. In November 1998, SUGEN entered into a collaboration with the Cancer Research Campaign (CRC) to conduct a phase I trial of SU-6668 at the Royal Marsden Hospital, UK using an iv formulation [304530]. After the first six patients had been treated, the trial was halted owing to problems with the iv formulation. Some toxicities, including nausea, vomiting, fatigue and tumor pain were observed [413538]. No licensing agreement as involved between the CRC and SUGEN for this trial [408572].
Topics: Animals; Antineoplastic Agents; Enzyme Inhibitors; Humans; Indoles; Neoplasms; Oxindoles; Propionates; Protein-Tyrosine Kinases; Pyrroles; Structure-Activity Relationship
PubMed: 11892927
DOI: No ID Found -
Journal of Surgical Oncology Aug 2004Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis of many solid malignancies. The influence of angiogenesis and VEGF expression on... (Review)
Review
Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis of many solid malignancies. The influence of angiogenesis and VEGF expression on progression and recurrence of esophageal cancer has been investigated over the last years. This article reviews the prognostic significance of VEGF expression, microvessel density (MVD), and lymphangiogenic factors in squamous cell carcinoma (SCC), Barrett's dysplasia, and adenocarcinoma (AC) of the esophagus, their predictive value for treatment response to chemo-radiotherapy and new anti-angiogenic treatment strategies.
Topics: Adenocarcinoma; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Barrett Esophagus; Bevacizumab; Carcinoma, Squamous Cell; Esophageal Neoplasms; Humans; Indoles; Lymphangiogenesis; Neovascularization, Pathologic; Oxindoles; Prognosis; Propionates; Protein-Tyrosine Kinases; Pyrroles; RNA, Catalytic; RNA, Messenger; Vascular Endothelial Growth Factor A
PubMed: 15282704
DOI: 10.1002/jso.20070 -
Human Cell Oct 2020Alveolar soft-part sarcoma is a mesenchymal malignancy characterized by the rearrangement of ASPSCR1 and TFE3 and a histologically distinctive pseudoalveolar pattern....
Alveolar soft-part sarcoma is a mesenchymal malignancy characterized by the rearrangement of ASPSCR1 and TFE3 and a histologically distinctive pseudoalveolar pattern. Although alveolar soft-part sarcoma takes an indolent course, its long-term prognosis is poor because of late distant metastases. Currently, curative treatments have not been found for alveolar soft-part sarcoma, and hence, a novel therapeutic strategy has long been required. Patient-derived cell lines comprise an important tool for basic and preclinical research. However, few cell lines from alveolar soft-part sarcoma have been reported in the literature because it is an extremely rare malignancy, accounting for less than 1% of all soft-tissue sarcomas. This study aimed to establish a novel alveolar soft-part sarcoma cell line. Using surgically-resected tumor tissue of alveolar soft-part sarcoma, we successfully established a cell line and named it NCC-ASPS1-C1. The NCC-ASPS1-C1 cells harbored an ASPSCR1-TFE3 fusion gene and exhibited slow growth, and spheroid formation. On the other hand, NCC-ASPS1-C1 did not show the capability of invasion. We screened the antiproliferative effects of 195 anticancer agents, including Food and Drug Administration-approved anticancer drugs. We found that the MET inhibitor tivantinib and multi-kinase inhibitor orantinib inhibited the proliferation of NCC-ASPS1-C1 cells. The clinical utility and molecular mechanisms of antitumor effects of these drugs are worth investigating in the further studies, and NCC-ASPS1-C1 cells will be a useful tool for the in vitro study of alveolar soft-part sarcoma.
Topics: Antineoplastic Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Culture Techniques; Cell Line, Tumor; Drug Discovery; Drug Screening Assays, Antitumor; Gene Fusion; Humans; Intracellular Signaling Peptides and Proteins; Male; Medical Oncology; Middle Aged; Sarcoma, Alveolar Soft Part
PubMed: 32648033
DOI: 10.1007/s13577-020-00382-2 -
Current Hematology Reports Jan 2005Acute myelogenous leukemia (AML) is a difficult disease to treat. Novel treatment strategies, including molecular targeted therapy, are currently being explored. The... (Review)
Review
Acute myelogenous leukemia (AML) is a difficult disease to treat. Novel treatment strategies, including molecular targeted therapy, are currently being explored. The c-kit receptor represents a potential therapeutic target for AML. The receptor is expressed on more than 10% of blasts in 64% of de novo AMLs and 95% of relapsed AMLs. C-kit mediates proliferation and anti-apoptotic effects in AML. This review will discuss the biology of c-kit in normal and malignant hematopoiesis, and the recent clinical trials targeting c-kit in AML.
Topics: Acute Disease; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Clinical Trials as Topic; Hematopoiesis; Humans; Imatinib Mesylate; Indoles; Leukemia, Myeloid; Mice; Oxindoles; Piperazines; Propionates; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-kit; Pyrimidines; Pyrroles; Stem Cell Factor
PubMed: 15610660
DOI: No ID Found