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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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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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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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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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AST-120 (spherical carbon adsorbent) in the treatment of perianal fistulae in mild-to-moderate Crohn's disease: FHAST-1, a phase 3, multicenter, placebo-controlled study.
Reinisch, W, Travis, S, Hanauer, S, Wang, H, Shara, N, Harris, MS
Inflammatory bowel diseases. 2014;(5):872-81
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BACKGROUND AST-120 (spherical carbon adsorbent) was previously reported to be effective for perianal fistula healing in Japanese patients with mild-to-moderate Crohn's disease. METHODS To evaluate the efficacy and safety of AST-120 in a Western population, a phase 3, multicenter, randomized, double-blind, placebo-controlled, study (FHAST-1) was conducted in adult patients with at least 1 draining perianal fistula and a Crohn's disease activity index <400. Patients received either AST-120 or matching placebo at a dose of 2 g 3 times daily for 8 weeks. The primary endpoint was the proportion of patients with treatment success, defined as a 50% reduction in the number of draining fistulae, at both weeks 4 and 8. A multivariate model was generated to assess covariates for treatment success among baseline variables. RESULTS Two hundred forty-nine patients were randomized (AST-120; n = 122; placebo, n = 127). The proportions of patients achieving the primary endpoint were no different between treatment groups (13.9% versus 16.5%, P = 0.6). No differences in fistula response were noted at week 4 (23.0% versus 25.2%, P = 0.77) or week 8 (27.0 versus 34.6%, P = 0.22). Serum C-reactive protein concentrations >0.6 mg/dL and Crohn's disease activity index scores >151 at baseline were associated with a reduced likelihood of treatment success (odds ratio, 0.40; confidence interval, 0.19-0.87; P = 0.02; and odds ratio, 0.45; confidence interval, 0.21-0.97; P = 0.04, respectively). CONCLUSIONS In this largest placebo-controlled trial to date to evaluate the impact of a therapeutic agent on perianal fistulae in Crohn's disease, the efficacy of AST-120 could not be confirmed. An inverse relationship was observed between both inflammatory and clinical disease activity and fistula response.
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Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype.
Poiré, X, Moser, BK, Gallagher, RE, Laumann, K, Bloomfield, CD, Powell, BL, Koval, G, Gulati, K, Holowka, N, Larson, RA, et al
Leukemia & lymphoma. 2014;(7):1523-32
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The addition of arsenic trioxide (ATO) to frontline therapy of acute promyelocytic leukemia (APL) has been shown to result in significant improvements in disease-free survival (DFS). FLT3 mutations are frequently observed in APL, but its prognostic significance remains unclear. We analyzed 245 newly diagnosed adult patients with APL treated on intergroup trial C9710 and evaluated previously defined biological and prognostic factors and their relationship to FLT3 mutations and to additional karyotypic abnormalities. FLT3 mutations were found in 48% of patients, including 31% with an internal tandem duplication (FLT3-ITD), 14% with a point mutation (FLT3-D835) and 2% with both mutations. The FLT3-ITD mutant level was uniformly low, < 0.5. Neither FLT3 mutation had an impact on remission rate, induction death rate, DFS or overall survival (OS). The addition of ATO consolidation improved outcomes regardless of FLT3 mutation type or level, initial white blood cell count, PML-RARA isoform type or transcript level. The presence of a complex karyotype was strongly associated with an inferior OS independently of post-remission treatment. In conclusion, the addition of ATO to frontline therapy overcomes the impact of previously described adverse prognostic factors including FLT3 mutations. However, complex karyotype is strongly associated with an inferior OS despite ATO therapy.
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Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia.
Yanada, M, Tsuzuki, M, Fujita, H, Fujimaki, K, Fujisawa, S, Sunami, K, Taniwaki, M, Ohwada, A, Tsuboi, K, Maeda, A, et al
Blood. 2013;(16):3095-102
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The optimal treatments for relapsed acute promyelocytic leukemia (APL) remain equivocal. We conducted a phase 2 study to evaluate the efficacy and feasibility of a sequential treatment consisting of induction and consolidation with arsenic trioxide (ATO), peripheral blood stem cell (PBSC) harvest after high-dose cytarabine chemotherapy, and autologous hematopoietic cell transplantation (HCT). Between 2005 and 2009, 35 patients (26 with hematologic and 9 with molecular relapse) were enrolled. Induction therapy resulted in complete remission in 81% of those with hematologic relapse, and most patients became negative for PML-RARα after the first ATO consolidation course, but 4 remained positive. Administration of the second ATO consolidation course further decreased the transcript levels in 3 patients. In total, 25 patients proceeded to PBSC harvest, all of whom successfully achieved the target CD34+ cell doses, and 23 underwent autologous HCT with PML-RARα-negative PBSC graft. Posttransplant relapse occurred in 3 patients, and there was no transplant-related mortality. With a median follow-up of 4.9 years, the 5-year event-free and overall survival rates were 65% and 77%, respectively. These findings demonstrate the outstanding efficacy and feasibility of the sequential treatment featuring ATO and autologous HCT for relapsed APL. This study was registered at http://www.umin.ac.jp/ctr/ as #C000000302.
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Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era.
Ramadan, SM, Di Veroli, A, Camboni, A, Breccia, M, Iori, AP, Aversa, F, Cupelli, L, Papayannidis, C, Bacigalupo, A, Arcese, W, et al
Haematologica. 2012;(11):1731-5
Abstract
The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed.
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Arsenic trioxide in patients with refractory multiple myeloma: a prospective, phase II, single-arm study.
Sanaat, Z, Rezazadeh, M, Gharamaleki, JV, Ziae, JE, Esfahani, A
Acta medica Iranica. 2011;(8):504-8
Abstract
Multiple myeloma (MM) characterized by proliferation of plasma cells in bone marrow and production of monoclonal immunoglobulin's. Recently, arsenic trioxide (ATO), has been considered for treatment refractory MM. We assessed the safety and efficacy of ATO for patients with refractory MM. A phase 2, study of arsenic trioxide was conducted in 12 MM patients, whose refractory to two standard therapy. Patients received arsenic trioxide, 0.25 mg/kg/d for 5 d/week during the first 2 consecutive weeks of each 4-week cycle with 2 week rest. Patients who completed one 4-week cycle were evaluated for response to treatment. Twelve patients with refractory multiple myeloma received ATO. Disease assessment was based the amount of serum proteins electrophoresis. Of the10 patients; stable disease was observed in four patients(33%), progression disease in five patients (41.6%), complete response in one patient (3.8%) and the remaining two patients could not be assessed for a response (because of increased liver enzymes after the first week). Some adverse events: increase liver enzymes and serum creatinine, neutropenia, pruritus, nausea, vomiting, lower extremities edema, noninfectious diarrhea was observed. These results indicate that ATO is active and well tolerated as a single-agent salvage therapy, even in patients with late-stage, refractory MM.