ABSTRACT
BACKGROUND: Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. PATIENTS AND METHODS: Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. RESULTS: Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. CONCLUSIONS: Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.
Subject(s)
Antibodies , Antineoplastic Agents , Immunoconjugates , Neoplasms , Adolescent , Adult , Antibodies/adverse effects , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Bayes Theorem , Cell Adhesion Molecules , Dose-Response Relationship, Drug , Humans , Immunoconjugates/adverse effects , Immunoconjugates/pharmacokinetics , Maximum Tolerated Dose , Neoplasms/drug therapy , Neoplasms/pathology , Treatment OutcomeABSTRACT
Melatonin receptors can inhibit breast and prostate cancers; however, little is known regarding their effects on oral squamous cell carcinoma. In this study, we collected specimens from 81 patients with oral squamous cell carcinoma and analysed clinicopathological data retrospectively. In addition, the expression of the melatonin receptor was analysed immunohistochemically. Survival rates were calculated using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed based on the Cox proportional-hazards model. Further, an in vitro study was performed using YD15 cells. The cells were transfected with siRNA targeting melatonin receptor 1A and 1B for evaluating the malignancy of melatonin receptors by western blotting, trypan blue-exclusion, colony-forming, wound-healing, and invasion assays. Survival decreased as melatonin receptor expression and clinical and pathological tumour-node-metastasis stages increased. A Cox proportional-hazard model showed that melatonin receptor 1A may serve as a significant predictor of the survival rate of patients with oral squamous cell carcinoma [hazard ratio = 1.423, 95% confidence interval (CI) = 1.019-1.988, p = 0.038]. Melatonin receptor 1A and 1B knockdown significantly suppressed proliferation, migration ability, and invasion ability of YD15 cells in vitro. Our findings reveal that inhibiting melatonin receptor expression may suppress oral squamous cell carcinoma development.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Melatonin , Mouth Neoplasms , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/therapy , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Mouth Neoplasms/genetics , Mouth Neoplasms/therapy , Prognosis , Proportional Hazards Models , Receptors, Melatonin , Retrospective Studies , Squamous Cell Carcinoma of Head and NeckABSTRACT
BACKGROUND: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. PATIENTS AND METHODS: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. RESULTS: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). CONCLUSION: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/therapeutic use , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/genetics , Humans , Paclitaxel/therapeutic useABSTRACT
BACKGROUND: Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated. PATIENTS AND METHODS: Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. RESULTS: Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0-78.2) with nivolumab plus SOX and 76.5% (50.1-93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8-NR) and 10.6 months (5.6-12.5), respectively. CONCLUSION: Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX. CLINICALTRIALS.GOV ID: NCT02746796.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophagogastric Junction/drug effects , Neoplasm Recurrence, Local/drug therapy , Stomach Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Capecitabine/administration & dosage , Drug Combinations , Esophagogastric Junction/pathology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Nivolumab/administration & dosage , Oxaliplatin/administration & dosage , Oxonic Acid/administration & dosage , Prognosis , Stomach Neoplasms/pathology , Survival Rate , Tegafur/administration & dosageABSTRACT
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
Subject(s)
Esophageal Neoplasms , Humans , Asia , Consensus , Disease Management , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/secondary , Esophageal Neoplasms/therapy , Societies, MedicalABSTRACT
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of gastric cancer (GC) was published in 2016, and covered the management and treatment of local, locoregional, locally advanced and metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and The Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic GC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic GC representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
Subject(s)
Stomach Neoplasms , Humans , Asia , Consensus , Disease Management , Societies, Medical , Stomach Neoplasms/diagnosis , Stomach Neoplasms/secondary , Stomach Neoplasms/therapyABSTRACT
Background: There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC. Patients and methods: Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician's choice of chemotherapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 or irinotecan 150 mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Results: A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9-1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4-2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm. Conclusions: Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy. Trial registration: ClinicalTrials.gov: NCT02625623.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Choice Behavior , Esophageal Neoplasms/drug therapy , Esophagogastric Junction/pathology , Neoplasm Recurrence, Local/drug therapy , Practice Patterns, Physicians'/statistics & numerical data , Stomach Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma, Mucinous/drug therapy , Adenocarcinoma, Mucinous/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Carcinoma, Papillary/drug therapy , Carcinoma, Papillary/pathology , Carcinoma, Signet Ring Cell/drug therapy , Carcinoma, Signet Ring Cell/pathology , Decision Support Techniques , Esophageal Neoplasms/pathology , Female , Follow-Up Studies , Humans , International Agencies , Irinotecan/administration & dosage , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Paclitaxel/administration & dosage , Prognosis , Stomach Neoplasms/pathology , Survival Rate , Young AdultABSTRACT
Background: Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. Methods and materials: Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. Results: Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). Conclusions: DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.gov: NCT01839773.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Paclitaxel/administration & dosage , Stomach Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease-Free Survival , Drug Resistance, Neoplasm/drug effects , Female , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Response Evaluation Criteria in Solid Tumors , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival AnalysisABSTRACT
BACKGROUND: Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3) was developed. PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/m(2)/day on days 1-14 and cisplatin 60 mg/m(2) on day 1) was noninferior/superior to SP5 (S-1 80-120 mg/day on days 1-21 and cisplatin 60 mg/m(2) on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382). RESULTS: Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3-48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months; hazard ratio (HR) = 0.82; 95% confidence interval (CI) 0.68-0.99; P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months; HR = 0.99; 95% CI 0.81-1.21; P = 0.9068). In patients with measurable disease, the response rates were 60% in the SP3 arm and 50% in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19% versus 9%) and neutropenia (39% versus 9%) were more frequent in SP3. CONCLUSIONS: SP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Stomach Neoplasms/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Cisplatin/administration & dosage , Drug Administration Schedule , Drug Combinations , Follow-Up Studies , Humans , Lymphatic Metastasis , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Oxonic Acid/administration & dosage , Prognosis , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Rate , Tegafur/administration & dosageABSTRACT
BACKGROUND: The TNM classification system is used widely for tumour staging, and directs the treatment and prognosis of patients with cancer. The aim of this study was to assess the prognostic value of extranodal extension (ENE) in patients with early gastric cancer. METHODS: All patients who underwent gastrectomy with lymphadenectomy for primary gastric cancer with lymph node metastases between January 2003 and June 2006 were reviewed. Histological slides of metastatic nodes were reviewed by two gastrointestinal pathologists. The association of ENE with clinicopathological characteristics was assessed. The disease-specific survival rate was calculated by the Kaplan-Meier method, and a multivariable Cox regression model was used to identify independent prognostic factors. RESULTS: Some 1143 patients were included. ENE was associated with advanced pT and pN category, larger tumour size and lymphovascular/perineural invasion. In multivariable analysis, pT category, pN category, ENE, lymphovascular invasion and perineural invasion were found to be independent prognostic factors in node-positive gastric carcinoma. The 5-year survival rate of patients with ENE was 48·1 per cent, compared with 78·2 per cent for patients without ENE (P < 0·001). In the subgroup of patients with early gastric cancer, ENE was associated with a worse 5-year survival rate in patients with early (T1) gastric cancer: 75 per cent in patients with ENE versus 96·9 per cent in those without (P < 0·001). CONCLUSION: ENE is an independent prognostic factor in patients with early and advanced gastric cancer.
Subject(s)
Stomach Neoplasms/pathology , Adult , Aged, 80 and over , Disease-Free Survival , Female , Gastrectomy/methods , Gastrectomy/mortality , Humans , Lymph Node Excision/methods , Lymph Node Excision/mortality , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Prognosis , Retrospective Studies , Stomach Neoplasms/mortality , Stomach Neoplasms/surgery , Young AdultABSTRACT
BACKGROUND: An exploratory translational analysis was conducted as part of a phase II study of dovitinib to assess the relevance of soluble serum proteins and circulating tumor (ct) DNA (ctDNA) as biomarkers in patients with tyrosine kinase inhibitor (TKI)-refractory gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS: Predose serum samples were collected from 30 patients on day 1 of cycle 1 and cycle 2. Serum levels of angiogenesis-related proteins were assessed by enzyme-linked immunosorbent assay, and Beads, emulsions, amplification, and magnetics (BEAMing) assays were carried out to detect mutations in serum ctDNA. RESULTS: Dovitinib increased vascular endothelial growth factor (VEGF)165 (1.26-fold, P = 0.006), VEGF-A (1.27-fold, P = 0.004), placental growth factor (6.0-fold, P = 0.002), fibroblast growth factor 23 (1.45-fold, P = 0.02), and interleukin 8 (1.75-fold, P = 0.04) levels, and decreased soluble vascular endothelial growth factor receptor (sVEGFR)-2 levels (0.8-fold, P = 0.001). The changes in sVEGFR-2 were significantly associated with metabolic response determined by positron emission tomography (P = 0.02) and progression-free survival (PFS; P = 0.02). Secondary kinase mutations were identified in the ctDNA of 11 patients (41%), and these patients all had mutations involving KIT exon 17. Patients with secondary KIT mutations had significantly worse overall survival {median, 5.5 months [95% confidence interval (CI) 3.8-7.2 months]} than those with no detectable secondary mutations [9.8 months (95% CI 9.6-10.0 months); hazard ratio = 2.7 (95% CI 1.0-7.3); P = 0.047]. CONCLUSIONS: Changes in sVEGFR-2 levels were associated with dovitinib-mediated antitumor activity. Genotyping of serum ctDNA with BEAMing is useful for the identification of resistant mutations potentially associated with poor prognosis in patients with GISTs.
Subject(s)
Benzimidazoles/administration & dosage , Biomarkers, Tumor/blood , Gastrointestinal Stromal Tumors/blood , Gastrointestinal Stromal Tumors/drug therapy , Quinolones/administration & dosage , Adult , Aged , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , Disease-Free Survival , Female , Gastrointestinal Stromal Tumors/pathology , Humans , Male , Middle Aged , Neoplastic Cells, Circulating/pathology , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins B-raf/blood , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-kit/blood , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor beta/blood , Receptor, Platelet-Derived Growth Factor beta/genetics , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor Receptor-2/bloodABSTRACT
BACKGROUND: This prospective, phase II trial evaluated the efficacy and safety of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours (GISTs) after failure of at least imatinib and sunitinib. METHODS: Patients received oral dovitinib, 500 mg once daily, for 5 consecutive days, followed by a 2-day rest, every 28 days. The primary endpoint was disease control rate (DCR; objective response+stable disease (SD)) at 24 weeks, assessed by computed tomography (CT) scan according to RECIST v1.0. Metabolic response was evaluated by positron emission tomography (PET)-CT scans performed at baseline and after 4 weeks of treatment. RESULTS: Between September 2011 and April 2012, 30 patients were enrolled. DCR at 24 weeks by RECIST v1.0 was 13% and one patient (3%) had a partial response. Based on the European Organization for Research and Treatment of Cancer PET response criteria, four patients (13%) had a metabolic partial response after 4 weeks of treatment. At a median follow-up of 8.3 months (range, 6.3-12.2 months), median progression-free survival (PFS) was 3.6 months (95% confidence interval (CI), 3.5-3.7 months) and median overall survival was 9.7 months (95% CI, 6.0-13.4 months). Metabolic progressive disease at Week 4 was significantly associated with shorter PFS (P=0.03). Grade 3/4 adverse events included asthenia (20%), neutropenia (13%), thrombocytopenia (10%), and hypertriglyceridaemia (10%). Most toxicities were manageable by dose modification. CONCLUSION: Dovitinib showed modest antitumour activity with manageable toxicities in heavily pretreated patients with advanced GISTs.
Subject(s)
Benzimidazoles/administration & dosage , Gastrointestinal Stromal Tumors/drug therapy , Quinolones/administration & dosage , Administration, Oral , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Benzimidazoles/adverse effects , Benzimidazoles/pharmacokinetics , Disease Progression , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Gastrointestinal Stromal Tumors/metabolism , Humans , Imatinib Mesylate , Indoles/therapeutic use , Male , Middle Aged , Piperazines/therapeutic use , Prospective Studies , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Quinolones/adverse effects , Quinolones/pharmacokinetics , SunitinibABSTRACT
BACKGROUND: Many patients with refractory or relapsed gastric cancer after first-line chemotherapy have received salvage chemotherapy in routine clinical practice. However, there was no evidence to support this treatment until recent phase III trials demonstrated substantial prolongation of overall survival. Therefore, we conducted a meta-analysis of these trials and investigated whether second-line chemotherapy was more effective than best supportive care. PATIENTS AND METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2013), MEDLINE (1950 to March week 4, 2013) and EMBASE (1980-2013, week 13). In addition, we searched all abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held between 2004 and 2013. RESULTS: The search process yielded 578 studies, two of which were randomized phase III trials that compared chemotherapy with supportive care. From the abstracts and virtual meeting presentations of ASCO held between 2004 and 2013, 127 abstracts were identified that evaluated second-line chemotherapy; only one relevant abstract was included in the meta-analysis. A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy, and 81 received irinotecan chemotherapy. A significant reduction in the risk of death [HR = 0.64, 95% confidence interval (CI) 0.52-0.79, P < 0.0001] was observed with salvage chemotherapy. When the analysis was restricted to irinotecan or docetaxel, there was still significant reduction in the risk of death with each chemotherapeutic agent. The HR was 0.55 (95% CI 0.40-0.77, P = 0.0004) for irinotecan and 0.71 (95% CI 0.56-0.90, P = 0.004) for docetaxel. CONCLUSION: This meta-analysis demonstrated evidence to support second-line chemotherapy in advanced gastric cancer.
Subject(s)
Camptothecin/analogs & derivatives , Stomach Neoplasms/drug therapy , Taxoids/administration & dosage , Antineoplastic Agents/administration & dosage , Camptothecin/administration & dosage , Clinical Trials, Phase III as Topic , Docetaxel , Fluorouracil/administration & dosage , Humans , Irinotecan , Neoplasm Recurrence, Local/drug therapy , Neoplasm Staging , Randomized Controlled Trials as Topic , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer. PATIENTS AND METHODS: A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II-IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 3 months) or MFP (MMC 20 mg m(-2), followed by oral doxifluridine 460-600 mg m(-2) per day for 12 months with 6 monthly infusions of 60 mg m(-2) of cisplatin) chemotherapy. RESULTS: With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89-1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89-1.39); P=0.33). CONCLUSION: Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Stomach Neoplasms/drug therapy , Adolescent , Adult , Aged , Cisplatin/administration & dosage , Female , Floxuridine/administration & dosage , Follow-Up Studies , Gastrectomy , Humans , Lymphatic Metastasis , Male , Middle Aged , Mitomycin/administration & dosage , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/surgery , Neoplasm Staging , Prognosis , Prospective Studies , Stomach Neoplasms/mortality , Stomach Neoplasms/surgery , Survival Rate , Time Factors , Young AdultABSTRACT
BACKGROUND: To assess the efficacy and safety of individualised dose optimisation of irinotecan monotherapy as salvage treatment for advanced gastric cancer (AGC). METHODS: A total of 43 patients were enrolled. Intravenous irinotecan (350 mg m(-2)) was administered every 3 weeks. The dose was increased (425 mg m(-2) and 500 mg m(-2)) or decreased (250 mg m(-2)) depending on patient tolerance. UGT1A1 genotypes were determined by direct sequencing of genomic DNA extracted from peripheral blood. RESULTS: A total of 183 cycles of irinotecan were administered, with a median of four cycles per patient. The overall response rate was 9.3%, and the disease control rate was 62.8%. Median time to disease progression was 2.8 months, and median overall survival was 8.0 months. Grade 3-4 neutropenia was the most common toxicity (53.5%), and febrile neutropenia was the least common toxicity (4.6%). Compared with defective allele groups, UGT1A1 *1/*1 was associated with a lower incidence of grade 3-4 neutropenia during the first cycle (P=0.018). CONCLUSION: Individualised irinotecan dose escalation based on patient tolerance was not associated with increased toxicity and shows modest activity as salvage chemotherapy for AGC. The role of UGT1A1 genotype in clinical toxicity requires further evaluation.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Camptothecin/analogs & derivatives , Glucuronosyltransferase/genetics , Salvage Therapy , Stomach Neoplasms/drug therapy , Adult , Antineoplastic Agents, Phytogenic/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Female , Genotype , Humans , Irinotecan , Male , Middle Aged , Stomach Neoplasms/genetics , Stomach Neoplasms/mortalityABSTRACT
BACKGROUND: To evaluate the activity and safety of everolimus and identify potential biomarkers for efficacy of everolimus in patients with advanced gastric cancer (AGC), who failed both fluoropyrimidine and platinum. METHODS: Fifty-four patients received everolimus (10 mg day(-1)). The primary objective was to determine the 4-month progression-free survival (PFS) rate, assumed to be 30%. We additionally investigated the potential biomarkers for everolimus as an exploratory endpoint in those who underwent tumour biopsies. RESULTS: Two patients (3.7%) achieved partial response and the disease control rate (DCR) was 38.9%. At a median follow-up duration of 8.7 months, the 4-month PFS rate was 18.4%, not fulfilling the primary hypothesis, with a median PFS of 1.7 months and a median overall survival of 8.3 months. The high expression of pS6(Ser240/4) at baseline was significantly associated with higher DCR (P=0.043) and prolonged PFS (P=0.001). Grade 1/2 asthenia (96.3%) recorded as the leading toxicity and hyperglycaemia (20.4%) was the most common non-hematological grade 3/4 toxicity. Three patients experienced grade 3/4 pneumonitis. Notably, two experienced treatment-related deaths. CONCLUSION: Everolimus is active against a limited number of patients with AGC. pS6(Ser240/4) may be a potential predictive biomarker for everolimus, which requires validation. Careful monitoring is necessary despite generally favourable toxicity profile.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/metabolism , Drug Resistance, Neoplasm , Fluorouracil/pharmacology , Platinum Compounds/pharmacology , Sirolimus/analogs & derivatives , Stomach Neoplasms/drug therapy , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Adult , Aged , Antineoplastic Agents/adverse effects , Disease-Free Survival , Everolimus , Female , Fluorouracil/therapeutic use , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Patient Dropouts , Platinum Compounds/therapeutic use , Sirolimus/adverse effects , Sirolimus/therapeutic use , Stomach Neoplasms/metabolism , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Treatment OutcomeABSTRACT
PURPOSE: To evaluated the efficacy and safety of sorafenib in patients with advanced gastrointestinal stromal tumors (GIST) who failed to previous standard treatments. EXPERIMENTAL DESIGN: Thirty-one patients with measurable metastatic GIST who failed both imatinib and sunitinib were accrued. Sorafenib was administered orally at 400 mg twice daily until disease progression or development of intolerance. The primary endpoint was disease control rate (response + stable disease, DCR) at 24 weeks. RESULTS: Sorafenib was well tolerated, with hand-foot skin reaction, fatigue, hypertension, and abdominal pain being the most frequent adverse events. The relative dose intensity of sorafenib during the first 6 months was >80%. Four patients achieved partial response (response rate 13%, 95% CI 1-25%), and 16 (52%) had stable disease. DCR at 24 weeks was measured as 36% (95% CI 19-52%). Median progression-free and overall survivals were 4.9 and 9.7 months, respectively. Progression-free survival of patients with prior use of nilotinib (P = .0085) and with primary genotypes other than KIT exon 11 mutation (P = .0341) was significantly shorter than that of patients without. CONCLUSIONS: Sorafenib showed antitumor activity in this population of imatinib and sunitinib pretreated GIST. With sorafenib, about one third of patients can maintain disease control for more than 24 weeks.
Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Asian People , Drug Resistance, Neoplasm/drug effects , Female , Gastrointestinal Neoplasms/genetics , Gastrointestinal Stromal Tumors/genetics , Genotype , Humans , Male , Middle Aged , Mutation , Niacinamide/therapeutic use , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Sorafenib , Treatment OutcomeABSTRACT
The present study investigated the effect of inclusion of multi-microbe probiotic product on growth performance, apparent digestibility of nutrients, cecal microbiota and small intestinal morphology in broilers. Four hundred days-old Ross chicks were randomly allotted to five treatments on the basis of body weight (BW). Each treatment had four replicates of 20 chicks in each. Experimental diets were fed in two phases, starter (day 0-21) and finisher (day 22-35). Dietary treatments were; basal diet without any antimicrobial (NC), basal diet added with 20 mg Avilamycin/kg of diet (PC), 10(7) cfu multi-microbe probiotic/kg of diet (P1), 10(8) cfu multi-microbe probiotic/kg of diet (P2), and 10(9) cfu multi-microbe probiotic/kg of diet (P3). Overall BW gain and feed conversion ratio were better (p < 0.05) for treatments PC, P2 and P3 compared with NC and P1, with P1 being better (p < 0.05) than NC. Overall feed intake in treatments PC, P1, P2 and P3 were greater (p < 0.05) than NC. Apparent digestibility of dry matter and crude protein were greater (p < 0.05) in treatments PC, P2 and P3 compared with NC, with P1 being intermediate and not different form NC, PC, P2 and P3. At d 21 and 35, treatments PC, P1, P2 and P3 showed lower (p < 0.05) cecal Clostridium and Coliforms count in relation to NC. Moreover, cecal Clostridium (d 21) and Coliforms (d 21 and 35) count were lower (p < 0.05) in treatment PC in relation to P1; with P2 and P3 being intermediate and not different from PC. However, there was no effect of dietary treatments on cecal total anaerobic bacteria and Bifidobacterium spp. count. The villus height of duodenum in treatment PC was greater (p < 0.05) than NC, with P1, P2 and P3 being intermediate. Villus height of ileum in treatment PC was greater (p < 0.05) than in treatments P1 and NC, whereas it remained comparable among treatments PC, P2 and P3. Villus height to crypt depth ratio of ileum was greater (p < 0.05) for treatment PC, P2 and P3 compared with that in P1 and NC. It is concluded that multi-microbe probiotic inclusion at 10(8) and 10(9) cfu/kg diet had beneficial effects on broilers growth performance, apparent digestibility of nutrients and intestinal morphology and can be used as replacement to antibiotics growth promoter in broiler nutrition.
Subject(s)
Cecum/microbiology , Chickens/anatomy & histology , Digestion/drug effects , Intestine, Small/anatomy & histology , Intestine, Small/drug effects , Probiotics/pharmacology , Animal Feed , Animal Nutritional Physiological Phenomena , Animals , Diet/veterinary , Dietary SupplementsABSTRACT
Present study investigated the effect of dietary supplementation of Bacillus subtilis LS 1-2 on growth performance, apparent nutrient retention, caecal microbial population and intestinal morphology in broilers. Three hundred and twenty day-old Ross broiler chicks were randomly allotted to four treatments on the basis of BW in a randomized complete block design. Experimental diets were fed in two phases: starter (d 0-21) and finisher (d 22-35). Dietary treatments were basal diet supplemented with 0% (control), 0.15%, 0.30% and 0.45% B. subtilis LS 1-2. Supplementation of increasing levels of B. subtilis LS 1-2 showed linear improvement (P<0.05) in growth performance and apparent nutrient retention. At d 35, birds supplemented with increasing levels of B. subtilis LS 1-2 showed decrease in caecal Clostridium and Coliform count (linear, P<0.05). Moreover, supplementation of B. subtilis LS 1-2 increased (linear, P<0.05) villus height and villus height to crypt depth ratio in both duodenum and ileum. Results obtained in the present study indicate that B. subtilis LS 1-2 can be used as a growth promoter in broiler diets and can improve intestinal microbial balance and gut health of broilers.
Subject(s)
Bacillus subtilis , Cecum/microbiology , Chickens/growth & development , Intestine, Small/anatomy & histology , Probiotics , Animals , Chickens/anatomy & histology , Chickens/metabolism , Chickens/microbiology , Diet/veterinary , Dietary Supplements , Digestion/physiology , Intestine, Small/microbiologyABSTRACT
BACKGROUND: Advanced biliary cancer is often treated with fluoropyrimidine-based chemotherapy. In this study, we evaluated the efficacy and tolerability of a combination of S-1, an oral fluoropyrimidine prodrug, and oxaliplatin in patients with metastatic biliary cancer. METHODS: Patients with histologically confirmed metastatic biliary cancer and no history of radiotherapy or chemotherapy were enrolled. Oxaliplatin was administered intravenously (130 mg m(-2)), followed by 14-day administration of oral S-1 (40 mg m(-2) twice daily) with a subsequent 7-day rest period every 21 days. Pharmacokinetic analysis of S-1 was performed at cycle 1. Patients were genotyped for CYP2A6 polymorphisms ((*)1, (*)4, (*)7, (*)9 or (*)10), and pharmacokinetic and clinical parameters compared according to the CYP2A6 genotype. RESULTS: In total, 49 patients were evaluated, who received a median of four cycles. The overall response rate was 24.5%. Median progression-free and overall survival was 3.7 and 8.7 months, respectively. The most common haematological grade 3 out of 4 toxicity was neutropenia (14%), while non-hematological grade 3 out of 4 toxicities included anorexia (14%), nausea (12%), asthenia (10%), vomiting (10%), and diarrhoea (4%). Biotransformation of S-1 (AUC(0-24 h) of 5-fluorouracil/AUC(0-24 h) of tegafur) was 1.85-fold higher for the *1/*1 group than for the other groups (90% confidence interval 1.37-2.49). Diarrhoea (P=0.0740), neutropenia (P=0.396), and clinical efficacy (response rate, P=0.583; PFS, P=0.916) were not significantly associated with CYP2A6 genotype, despite differences in 5-FU exposure. CONCLUSION: The combination of S-1 and oxaliplatin appears to be active and well tolerated in patients with metastatic biliary cancer, and thus is feasible as a therapeutic modality. CYP2A6 genotypes are associated with differences in the biotransformation of S-1. However, the impact of the CYP2A6 polymorphism on variations in clinical efficacy or toxicity requires further evaluation.