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Phase I dose-escalation study of NBTXR3 activated by intensity-modulated radiation therapy in elderly patients with locally advanced squamous cell carcinoma of the oral cavity or oropharynx.
Hoffmann, C, Calugaru, V, Borcoman, E, Moreno, V, Calvo, E, Liem, X, Salas, S, Doger, B, Jouffroy, T, Mirabel, X, et al
European journal of cancer (Oxford, England : 1990). 2021;:135-144
Abstract
PURPOSE This phase I study assessed the safety of first-in-class radioenhancer nanoparticles, NBTXR3, in elderly or frail patients with locally advanced head and neck squamous cell carcinoma (HNSCC), ineligible for chemoradiation. METHODS Patients with stage III or IVA (American Joint Committee on Cancer (AJCC) guidelines, 7th edition, 2010) HNSCC of the oral cavity or oropharynx, aged ≥70 or ≥65 years and ineligible to receive cisplatin, amenable to radiotherapy (RT) with curative intent, received NBTXR3 as a single intratumoural (IT) injection followed by activation by intensity-modulated radiation therapy (IMRT; 70 Gy). The NBTXR3 dose corresponded to a percentage of the baseline tumour volume, measured by magnetic resonance imaging. The primary objectives were to determine the recommended phase II dose (RP2D), dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Safety and tolerability were assessed using National Cancer Institute CTCAE version 4.0. Antitumour activity was assessed by Response Evaluation Criteria in Solid Tumours 1.1. RESULTS Nineteen patients were enrolled: 3 at the dose level of 5%, 3 at the dose level of 10%, 5 at the dose level of 15% and 8 at the dose level of 22% of the tumour volume. The MTD was not reached, and no DLTs or serious adverse event (SAEs) related to NBTXR3 were observed. Four adverse events related to NBTXR3 and/or the IT injection were reported (grade I-II). NBTXR3 remained in the injected tumour throughout RT, with no leakage in the surrounding healthy tissues. Specific RT-related toxicity was as expected with IMRT. The RP2D was determined as 22% baseline tumour volume. Preliminary signs of antitumour activity were observed. CONCLUSION Intratumoural injection of NBTXR3 followed by IMRT is feasible and demonstrated a good safety profile, supporting further evaluation at the RP2D in this patient population. TRIAL REGISTRATION ClinicalTrials.govNCT01946867.
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A Pilot Study on the Effects of l-Carnitine and Trimethylamine-N-Oxide on Platelet Mitochondrial DNA Methylation and CVD Biomarkers in Aged Women.
Bordoni, L, Sawicka, AK, Szarmach, A, Winklewski, PJ, Olek, RA, Gabbianelli, R
International journal of molecular sciences. 2020;(3)
Abstract
l-carnitine supplementation has been used for cardiovascular health protection for a long time. Recently, trimethylamine-N-oxide (TMAO), which is an end product of l-carnitine metabolism via the activity of microbiota, has been identified as a cardiovascular disease (CVD) biomarker. The aim of this study was to assess the effect of 6 months of l-carnitine supplementation in a group of aged women engaged in a regular physical training. Platelet mitochondrial DNA methylation, an emerging and innovative biomarker, lipid profile and TMAO levels have been measured. TMAO increased after l-carnitine supplementation (before 344.3 ± 129.8 ng/mL vs. after 2216.8 ± 1869.0 ng/mL; n = 9; paired t-test, p = 0.02). No significant effects on TMAO were exerted by training alone (n = 9) or by l-leucine supplementation (n = 12). TMAO levels after 6 months of l-carnitine supplementation were associated with higher low-density lipoprotein-cholesterol (LDL-c) (Spearman Rho = 0.518, p = 0.003) and total cholesterol (TC) (Spearman Rho = 0.407, p = 0.026) levels. l-carnitine supplementation increased D-loop methylation in platelets (+6.63%; paired t-test, p = 0.005). D-loop methylation was not directly correlated to the TMAO augmentation observed in the supplemented group, but its increase inversely correlated with TC (Pearson coefficient = -0.529, p = 0.029) and LDL-c (Pearson coefficient = -0.439, p = 0.048). This evidence supports the hypothesis that the correlation between l-carnitine, TMAO and atherosclerosis might be more complex than already postulated, and the alteration of mitochondrial DNA (mtDNA) methylation in platelets could be involved in the pathogenesis of this multifactorial disease.
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NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.
Bonvalot, S, Rutkowski, PL, Thariat, J, Carrère, S, Ducassou, A, Sunyach, MP, Agoston, P, Hong, A, Mervoyer, A, Rastrelli, M, et al
The Lancet. Oncology. 2019;(8):1148-1159
Abstract
BACKGROUND Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING Nanobiotix SA.
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Predictive Factors for Efficacy of AST-120 Treatment in Diabetic Nephropathy: a Prospective Single-Arm, Open-Label, Multi-Center Study.
Hwang, YC, Kim, SW, Hur, KY, Cha, BS, Kim, IJ, Park, TS, Baik, SH, Yoon, KH, Lee, KW, Lee, IK, et al
Journal of Korean medical science. 2019;(15):e117
Abstract
BACKGROUND Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy. METHODS A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90. RESULTS Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; P = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 μol/L to 1.91 ± 0.72 μol/L; P = 0.002) but not in the non-responder group. CONCLUSION The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.
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Characteristics of fibrinolytic disorders in acute promyelocytic leukemia.
Wang, P, Zhang, Y, Yang, H, Hou, W, Jin, B, Hou, J, Li, H, Zhao, H, Zhou, J
Hematology (Amsterdam, Netherlands). 2018;(10):756-764
Abstract
OBJECTIVES Catastrophic hemorrhage remains the main cause of acute promyelocytic leukemia (APL) treatment failure. This study was aimed to study the pathogenesis of coagulopathy in patients with APL. METHODS Multiple procoagulant and profibrinolytic parameters in plasma and peripheral leukocytes from 24 patients with newly diagnosed APL accompanied by coagulopathy before and after arsenic trioxide (ATO) treatment were evaluated. RESULTS Prior to the treatment, the patients had elevated D-dimer and decreased fibrinogen levels. Plasma urokinase-type plasminogen activator receptor (uPAR) and plasmin-ɑ2 antiplasmin complexes (PAP) levels, plasmin (Pn) activity, and cell surface levels of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) were significantly higher; plasma plasminogen activator inhibitor-1 (PAI-1) levels and plasminogen (Pg) activity were significantly decreased; plasma plasminogen activator (PA) activity, uPA and tPA levels; and cell surface levels of uPAR and annexin II were not significantly different from levels in the control group. During ATO treatment, both patients' plasma PA activity and uPAR on leukocytes gradually increased, annexin II on leukocytes increased initially and decreased afterwards, and tPA and uPA on leukocytes remained consistently higher in the patients than in the controls. Other parameters gradually tended toward normal values. CONCLUSIONS In APL, activated coagulation system activated fibrinolytic system, and increased uPAR levels could contribute to the hyperfibrinolysis. Annexin II might not be involved in the coagulopathy.
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Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631.
Kutny, MA, Alonzo, TA, Gerbing, RB, Wang, YC, Raimondi, SC, Hirsch, BA, Fu, CH, Meshinchi, S, Gamis, AS, Feusner, JH, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;(26):3021-3029
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Abstract
Purpose The Children's Oncology Group AAML0631 trial for newly diagnosed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to determine the survival of patients receiving arsenic trioxide (ATO) consolidation and reduced doses of anthracyclines. Patients and Methods Patients age 2 to 21 years with de novo APL confirmed by PML-RARα polymerase chain reaction were stratified as standard risk (SR) or high risk (HR) on the basis of diagnostic WBC count. All patients received all-trans retinoic acid (ATRA) during induction, each consolidation course, and maintenance. All patients received two cycles of ATO therapy during consolidation 1, an additional two (SR) or three (HR) consolidation courses that included high-dose cytarabine and anthracycline, and maintenance therapy comprising ATRA, oral methotrexate, and mercaptopurine. Results One hundred one patients (66 SR and 35 HR) were evaluable for outcome. The 3-year overall survival was 94%, and event-free survival (EFS) was 91%. For SR and HR patients with APL, the overall survival was 98% versus 86% ( P = .003), and EFS was 95% versus 83% ( P = .03), respectively. The EFS for SR patients in AAML0631 was noninferior to that of patients in the AIDA 0493 historical control, which used a significantly higher anthracycline dose and did not include ATO consolidation. Relapse risk for patients in AAML0631 from end consolidation 1 (after ATO treatment) was only 4% at 3 years and did not differ significantly between SR and HR patients. Conclusion ATO consolidation cycles were well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anthracycline doses while maintaining excellent survival and a low relapse risk for both SR and HR patients with APL.
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The effects of AST-120 on chronic kidney disease progression in the United States of America: a post hoc subgroup analysis of randomized controlled trials.
Schulman, G, Berl, T, Beck, GJ, Remuzzi, G, Ritz, E, Shimizu, M, Shobu, Y, Kikuchi, M
BMC nephrology. 2016;(1):141
Abstract
BACKGROUND The orally administered spherical carbon adsorbent AST-120 is used on-label in Asian countries to slow renal disease progression in patients with progressive chronic kidney disease (CKD). Recently, two multinational, randomized, double-blind, placebo-controlled, phase 3 trials (Evaluating Prevention of Progression in Chronic Kidney Disease [EPPIC] trials) examined AST-120's efficacy in slowing CKD progression. This study assessed the efficacy of AST-120 in the subgroup of patients from the United States of America (USA) in the EPPIC trials. METHODS In the EPPIC trials, 2035 patients with moderate to severe CKD were studied, of which 583 were from the USA. The patients were randomly assigned to two groups of equal size that were treated with AST-120 or placebo (9 g/day). The primary end point was a composite of dialysis initiation, kidney transplantation, or serum creatinine doubling. RESULTS The Kaplan-Meier curve for the time to achieve the primary end point in the placebo-treated patients from the USA was similar to that projected before the study. The per protocol subgroup analysis of the population from the USA which included patients with compliance rates of ≥67 % revealed a significant difference between the treatment groups in the time to achieve the primary end point (Hazard Ratio, 0.74; 95 % Confidence Interval, 0.56-0.97). CONCLUSIONS This post hoc subgroup analysis of EPPIC study data suggests that treatment with AST-120 might delay the time to primary end point in CKD patients from the USA. A further randomized controlled trial in progressive CKD patients in the USA is necessary to confirm the beneficial effect of adding AST-120 to standard therapy regimens. TRIAL REGISTRATION ClinicalTrials.gov NCT00500682 ; NCT00501046 .
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Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial.
Iland, HJ, Collins, M, Bradstock, K, Supple, SG, Catalano, A, Hertzberg, M, Browett, P, Grigg, A, Firkin, F, Campbell, LJ, et al
The Lancet. Haematology. 2015;(9):e357-66
Abstract
BACKGROUND Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy. METHODS Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639. FINDINGS 124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4·2 years (IQR, 3·2-5·2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0·23 (95% CI 0·08-0·64, p=0·002) for freedom from relapse, 0·21 (0·07-0·59, p=0·001) for disease-free survival, 0·34 (0·16-0·69, p=0·002) for event-free survival, and 0·35 (0·14-0·91, p=0·02) for overall survival. INTERPRETATION Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival. FUNDING Phebra.
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[Efficacy Analysis of Arsenic Trioxide Combined with All Trans Retinoic Acid for Acute Promyelocytic Leukemia].
Wang, LL, Ren, YQ
Zhongguo shi yan xue ye xue za zhi. 2015;(5):1292-5
Abstract
OBJECTIVE To investigate the efficacy of arsenic trioxide combined with all trans retinoic acid (ATRA) for patients with acute promyelocytic leukemia (APL). METHODS A total of 159 cases of APL were selected from January 2011 to December 2014 in our hospital, among them 75 cases were treated by As₂O₃combined with ATRA, 43 cases were treated with As₂O₃alone, 41 cases were treated with ATRA alone. The cardiac enzymes level, lever function index change, death rate, complate remission (CR) rate, time of reaching CR and complicatiens were compared in 3 groups. RESULTS After treatment of 8 courses, ALT and AST levels in As₂O₃+ ATRA group were significantly higher than those in As₂O₃and ATRA alone groups; the CK-MB and TnI-UI index increased in As₂O₃group (P < 0.05); as compared with As₂O₃group, the mortality and CR rate in As₂O₃+ ATRA group were no significant different, but the time of reaching CR was significantly shortened. For relapsed patients, the CR rate in As₂O₃+ ATRA group was no significantly different from that in As₂O₃group, while was significantly higher than that in ATRA group. The ratio of liver function damage in As₂O₃+ ATRA group was increased, moreover the incidence of leukocytosis and headache in ATRA group was significantly higher than that in As₂O₃+ ATRA and As₂O₃group (P < 0.05). CONCLUSIONS The efficacy of As₂O₃conbined with ATRA for inducing remission is better than that of single drug treatment, moreover the adverse reactions occur less.
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Arsenic trioxide suppressed mantle cell lymphoma by downregulation of cyclin D1.
Lo, RK, Kwong, YL
Annals of hematology. 2014;(2):255-65
Abstract
Mantle cell lymphoma (MCL) is aggressive with poor prognosis. Due to t(11;14)(q13;q32), cyclin D1 is overexpressed. The in vitro activities of arsenic trioxide (As2O3) in MCL were investigated. In MCL lines Jeko-1 and Granta-519, As2O3 induced dose-dependent and time-dependent increases in apoptosis accompanied by cyclin D1 suppression. Downregulation of cyclin D1 resulted in decreased retinoblastoma protein phosphorylation, which led to repressed G1 progression to S/G2 phases. As2O3 did not affect cyclin D1 gene transcription. Instead, As2O3 activated glycogen synthase kinase-3beta (by tyrosine-216 phosphorylation) and IkappaB kinase alpha/beta (by serine-176/180 phosphorylation), both of which phosphorylated cyclin D1 at threonine-286, leading to its poly-ubiquitination and degradation in the proteasome. These observations were recapitulated partly in primary MCL samples obtained from patients refractory to conventional treatment. Our findings suggested that As2O3 might be clinically useful in MCL.