Cardiac Safety Assessment Study of Picoplatin in Solid Tumors
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ABSTRACT:
DISEASE(S): Ovarian Cancer,Lung Cancer,Colorectal Cancer,Bladder Cancer,Head And Neck Cancer,Pancreatic Cancer,Breast Cancer,Solid Tumors
PROVIDER: 2057868 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:PurposeTAS-102 is a novel oral agent combining the antineoplastic thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil (molar ratio 1:0.5). TAS-102 has shown good activity in refractory metastatic colorectal cancer with acceptable safety. No QT prolongation was seen in clinical studies. This study aimed to investigate TAS-102 cardiac safety for regulatory requirements.MethodsThis was a phase 1, non-randomized study in adults with advanced solid tumors. Intensive QT assessments were conducted at baseline, placebo, and following single and multiple doses of TAS-102 during a 28-day cycle.ResultsFollowing single- and multiple-dose administration (N = 30), the upper bounds of the one-sided 95 % confidence intervals for the difference between TAS-102 and placebo in time-matched baseline-subtracted 12-lead Holter QT intervals did not exceed 20 ms at any prespecified time point. One patient had a change from baseline in QTcI interval ≥60 ms, and one patient had a QTcI interval >500 ms following multiple-dose TAS-102 administration. No patient had an uncorrected QT, QTcF, or QTcB interval >500 ms. Based on the exposure-response analysis between TAS-102 plasma concentrations and the placebo-adjusted QTc intervals, none of the upper bounds of the one-sided 95 % prediction intervals exceeded 20 ms. There were no significant morphological changes for T or U waves. No cardiovascular AEs were reported in cycle 1. Across all cycles, no patient experienced an AE of ventricular tachycardia, ventricular fibrillation, syncope, or seizure.ConclusionsThere was no clinically relevant relationship between TAS-102 plasma concentrations and QTc interval; TAS-102 had no clinically relevant effects on cardiac repolarization.Clinical trialsClinicalTrials.gov study number: NCT01867879.
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Project description:Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin (DOXO), Aclarubicin (ACLA) and Amrubicin (AMR). DOXO and ACLA unlike AMR substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated with anthracyclines annually.
2023-10-01 | GSE232331 | GEO
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2016-11-30 | GSE90615 | GEO
Project description:To further investigate the role of hyaluronan and the regulation of its synthesis in cardiac hypertrophy, quantitative measurements of myocardial hyaluronan was correlated to gene transcription in hypertrophic cardiac tissue. Factor analysis was used to study correlation over time. Abdominal aorta was ligated in Wistar rats. Heart was excised 1 day, 6 days and 42 days after operation. Aorta ligated animals was compared to sham operated animals. N=6 in each time group, except aorta ligated after six days where n=5.
2010-05-27 | E-GEOD-21600 | biostudies-arrayexpress
Project description:ImportanceTherapies targeting the programmed cell death 1 (PD-1) receptor or its ligand (PD-L1), such as the humanized monoclonal antibody durvalumab, have shown durable clinical responses in several tumor types. However, concerns about the safety and feasibility of PD-1/PD-L1 blockade in HIV-1-infected individuals have led to the exclusion of these patients from clinical trials on cancer immunotherapies.ObjectiveTo evaluate the feasibility and safety of durvalumab treatment in patients with advanced cancer and virologically controlled HIV-1 infection.Design, setting, and participantsThe DURVAST study was a nonrandomized, open-label, phase 2 clinical trial in patients with any solid tumor type in which anti-PD-1 or anti-PD-L1 antibodies have approved indications or for which there are data of antitumoral activity with no other available curative therapy. All patients had basal undetectable plasma viremia while undergoing combination antiretroviral therapy.InterventionsTreatment consisted of intravenous infusion of durvalumab (1500 mg every 4 weeks) until disease progression or unacceptable toxic effects.Main outcomes and measuresAdverse events were graded with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 20 HIV-1-infected patients with advanced cancer were enrolled; 16 (80%) were male, the median (range) age was 54 (30-73) years, and 12 (60%) had progressed with previous cancer treatment lines. A median (range) of 4 (1-16) cycles of durvalumab were administered. Drug-related adverse events were observed in 50% of patients, and all were grade 1 and 2 (mainly diarrhea, asthenia, and arthromyalgia). Four of 16 response-evaluable patients (25%) had a partial response. Five patients (31%) had stable disease, including 4 with durable stable disease (disease control rate of 50%). CD4+ and CD8+ T-cell counts and plasma HIV-1 viremia remained stable throughout the study.Conclusions and relevanceDurvalumab treatment was feasible and safe in HIV-1-infected patients with cancer receiving combination antiretroviral therapy. HIV-1-infected patients on suppressive antiretroviral therapy with advanced cancer should have access to cancer immunotherapy treatments.Trial registrationClinicalTrials.gov Identifier: NCT03094286.
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Project description:Lessons learnedBintrafusp alfa had a manageable safety profile and demonstrated preliminary clinical activity in heavily pretreated patients with solid tumors (including hepatocellular carcinoma) with no or limited treatment options. Findings from this study suggest bintrafusp alfa may be a novel therapeutic approach for patients with advanced solid tumors. Additional trials are needed to further explore safety and efficacy of bintrafusp alfa in specific tumor types.BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor-β (TGF-β) RII receptor (a TGF-β "trap") fused to a human immunoglobulin (Ig) G1 antibody blocking programmed death-ligand 1 (PD-L1). Bintrafusp alfa is designed to neutralize TGF-β signaling by "trapping" and sequestering all TGF-β isoforms, and this trap function is physically linked to PD-L1 blockade in the tumor microenvironment.MethodsNCT02699515 was a phase I, open-label, dose-escalation study of bintrafusp alfa (3, 10, and 20 mg/kg every 2 weeks) in Asian patients with advanced solid tumors, including a hepatocellular carcinoma (HCC) safety-assessment cohort. The primary objective was safety and tolerability; the secondary objective is best overall response.ResultsAs of August 24, 2018, 23 patients (including 9 in the HCC cohort) received bintrafusp alfa. Eight patients experienced treatment-related adverse events (TRAEs). Three patients had grade 3 TRAEs (13.0%; hypoacusis, hyponatremia, hypopituitarism, increased blood creatine phosphokinase, and intracranial tumor hemorrhage); one had grade 4 hyponatremia (4.3%). No treatment-related deaths occurred. In the dose-escalation cohort, two patients had a confirmed partial response, and 3 had stable disease (SD), for an overall response rate of 14.3% and a disease control rate (DCR) of 35.7%. In the HCC cohort, one patient had SD (DCR, 11.1%). A dose-proportional pharmacokinetics profile was observed at doses of >3 mg/kg.ConclusionBintrafusp alfa had a manageable safety profile and preliminary efficacy in heavily pretreated patients with advanced solid tumors, including HCC.
| S-EPMC7485354 | biostudies-literature
Project description:IntroductionThe prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors.MethodsA systematic search of PubMed, Embase, and related articles was performed. Safety data were analyzed using Comprehensive Meta-Analysis software program version 2. Ultimately, 17 studies with 1,529 patients were included in our analysis.ResultsThe major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. Higher PD-L1 expression was associated with a superior objective response rate.ConclusionDurvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. PD-L1 expression is a biomarker of the efficacy of durvalumab.
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Project description:Purpose: To evaluate whether administration of the oral DNA hypomethylating agent (HMA) CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab.
2020-07-26 | GSE147537 | GEO
Project description:Purpose: In this study, we used RNA-Seq to characterize differences in the Left ventricle expression profiles rats with 62-week old submited to gestational protein restricion (LP) compared to normal protein (NP) offspring during de gestacional. Methods: Total RNA was extracted from left heart (rats with 62-week old submited to gestational protein restricion (LP) (n=5) compared to normal protein (NP) offspring during de gestacional) (n=5) using the Trizol methods. RNA concentration was quantitated using the NanoDrop. A library was built for each sample, using the TruSeq Stranded mRNA kit (illumina) and submitted to sequencing. Results: By genomic sequencing analysis, we verified changes in the expression of 137 genes; After gene to gene biological evaluation and relevance, the present study demonstrated significant differences in genes linked to inflammatory activity, oxidative stress, apoptosis process, autophagy and, in hypertrophy and fibrosis pathways resulting heart function disorders. Conclusion: The present study suggests that maternal protein restriction may lead to early heart disorders in the LP offspring compared to the NP group. We may hypothesize that rapid heart dysfunction is associated with heart fibrosis, myocardial cell hypertrophy and multiple gene expression abnormalities in the LP offspring.
2021-11-17 | GSE188836 | GEO
Project description:BACKGROUND:Vagus nerve stimulation has been successfully used as a treatment strategy for epilepsy and affective disorders for years. Transcutaneous vagus nerve stimulation (tVNS) is a new non-invasive method to stimulate the vagus nerve, which has been shown to modulate neuronal activity in distinct brain areas. OBJECTIVES:Here we report effects of tVNS on cardiac function from a pilot study, which was conducted to evaluate the feasibility and safety of tVNS for the treatment of chronic tinnitus. METHODS:Twenty-four patients with chronic tinnitus underwent treatment with tVNS over 3-10?weeks in an open single-armed pilot study. Safety criteria and practical usability of the neurostimulating device were to investigate by clinical examination and electrocardiography at baseline and at several visits during and after tVNS treatment (week 2, 4, 8, 16, and 24). RESULTS:Two adverse cardiac events (one classified as a severe adverse event) were registered but considered very unlikely to have been caused by the tVNS device. Retrospective analyses of electrocardiographic parameters revealed a trend toward shortening of the QRS complex after tVNS. CONCLUSION:To our knowledge this is one of the first studies investigating feasibility and safety of tVNS in a clinical sample. In those subjects with no known pre-existing cardiac pathology, preliminary data do not indicate arrhythmic effects of tVNS.
| S-EPMC3413045 | biostudies-literature