Senolytic Therapy for Frailty
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: St. Jude Children's Research Hospital
Must not be taking: CYP3A4 drugs, Anticoagulants
Disqualifiers: HIV, Hepatitis B/C, Anemia, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This is a first-in survivor pilot study with the goal of establishing preliminary evidence of efficacy, safety, and tolerability of two senolytic regimens to reduce markers of cellular senescence (primary outcome: p16\^INK4a) and improve frailty (primary outcome: walking speed) in adult survivors of childhood cancer. If successful, this pilot would provide the preliminary evidence needed for a phase 2, randomized, placebo-controlled trial to establish efficacy.
Primary Objective
* The primary aim of this proposal is to test the efficacy of two, short duration senolytic regimens: 1) combination of Dasatinib plus Quercetin and 2) Fisetin alone, to improve walking speed and decrease senescent cell abundance in blood (p16\^INKA):
* Primary endpoints of this trial will be change in walking speed and senescent cell abundance in blood (p16\^INK4A) determined at baseline and again at 60 days, within an individual arm. Extended follow up at 150 days will assess the permanence of change after completion of the trial. Secondary endpoints of this trial will be effect of intervention on additional measures of frailty (beyond walking speed; Fried criteria) and on other cell senescence markers, markers of inflammation, insulin resistance, bone resorption, and cognitive function.
Secondary Objectives
The secondary aim is to test the safety and tolerability of two different senolytic therapies.
Exploratory Objectives
* To compare the efficacy of the two senolytic regimens in improving walking speed and decreasing senescent cell abundance
* To evaluate the longitudinal pattern in measures of frailty.
Do I need to stop my current medications for the trial?
The trial requires you to stop taking certain medications, especially those that affect specific enzymes (CYP3A4, CYP2C8, CYP2C9, or CYP2D6) or if you are on anticoagulants or antimicrobial agents. If you are on anticoagulants or antiplatelet agents, you may need to pause them during the 2-3 day drug dosing period, but you can resume them afterward.
What data supports the effectiveness of the drug Dasatinib plus Quercetin for frailty?
Research in mice has shown that the combination of Dasatinib and Quercetin can improve frailty characteristics, motor and cognitive functions, and reduce signs of aging in the brain. Additionally, these drugs have been found to reduce senescent cells, which are linked to aging and frailty, in other studies.
12345Is senolytic therapy with dasatinib and quercetin safe for humans?
In early clinical trials, dasatinib and quercetin were generally well-tolerated in humans, with no early discontinuations and only mild to moderate side effects reported. These findings suggest a favorable safety profile, but more extensive studies are needed to confirm these results.
12567How is the drug Dasatinib plus Quercetin, Fisetin unique for treating frailty?
This drug combination is unique because it uses senolytic agents, which target and eliminate senescent cells (cells that have stopped dividing and can contribute to aging and frailty), potentially addressing the root cause of frailty rather than just its symptoms. Unlike standard treatments, this approach aims to improve overall health by reducing the burden of these harmful cells.
89101112Eligibility Criteria
Adults who survived childhood cancer and are now frail (meeting at least 3 of 5 specific health criteria), over 18 years old, more than 5 years post-diagnosis, with certain blood markers. They must be able to take oral meds, not pregnant or nursing, agree to use contraception due to teratogenic risks of Dasatinib, have no severe heart issues or anemia, and not on conflicting medications.Inclusion Criteria
QTc <450 milliseconds in electrocardiogram
I am part of SJLIFE and was diagnosed over 5 years ago.
My test shows low levels of a specific protein in my immune cells.
+7 more
Exclusion Criteria
I am currently taking blood thinners or antibiotics.
Pregnant or nursing at time of enrollment/during the study
I am not currently receiving treatment for any cancer except non-melanoma skin cancers.
+10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive either Dasatinib plus Quercetin or Fisetin to reduce senescence and improve frailty
32 days
6 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
150 days
2 visits (in-person)
Participant Groups
The trial is testing two treatments aimed at reducing cell aging and improving physical function in adult survivors of childhood cancer. One group will receive a combination of drugs called Dasatinib plus Quercetin; the other will get Fisetin alone. The main goals are better walking speed and fewer senescent cells in the blood.
2Treatment groups
Active Control
Group I: Dasatinib plus QuercetinActive Control1 Intervention
Day 0 (30 per arm, randomization stratified by sex and age)
At the visit on day 7, blood CD3+ T lymphocyte p16\^INK4A mRNA and other markers of inflammation and senescence will be accessed to verify that senescent cells have been cleared by the intervention.
Post-treatment follow-up will occur on days 60 for (primary endpoints) and day 150 for secondary evaluation. Day 150 will assess the permanence of change after completion of the trial.
Group II: FisetinActive Control1 Intervention
Day 0 (30 per arm, randomization stratified by sex and age)
At the visit on day 7, blood CD3+ T lymphocyte p16INK4A mRNA and other markers of inflammation and senescence will be accessed to verify that senescent cells have been cleared by the intervention.
Post-treatment follow-up will occur on days 60 for (primary endpoints) and day 150 for secondary evaluation. Day 150 to will assess the permanence of change after completion of the trial.
Dasatinib plus Quercetin is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as Sprycel for:
- Chronic Myelogenous Leukemia
- Acute Lymphoblastic Leukemia
🇺🇸 Approved in United States as Sprycel for:
- Chronic Myelogenous Leukemia
- Acute Lymphoblastic Leukemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
St. Jude Children's Research HospitalMemphis, TN
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Who Is Running the Clinical Trial?
St. Jude Children's Research HospitalLead Sponsor
National Institutes of Health (NIH)Collaborator
National Cancer Institute (NCI)Collaborator
References
Dasatinib plus quercetin attenuates some frailty characteristics in SAMP10 mice. [2022]Senolytics are a class of drugs that selectively remove senescent cells. Dasatinib and quercetin have been discovered, and their combination has shown various anti-ageing effects. The SAMP10 mouse strain is a model of brain ageing. Here, we investigated the effect of combination on frailty characteristics in SAMP10. By comparing SAMP10 with SAMR1 mice as normal ageing controls, we investigated some frailty characteristics. Frailty was assessed at 18-38 weeks of age with a clinical frailty index. Motor and cognitive function of these mice were evaluated using behavioral experiments. SAMP10 mice were divided into vehicle and combination, and these functions and histological changes in the brain hippocampus were investigated. Finally, the in vitro effects of combination on oxidative stress-induced senescent muscle and neuronal cells were investigated. As a result, we found that frailty index was higher in SAMP10 than SAMR1. Motor and cognitive function were worse in SAMP10 than SAMR1. Furthermore, combination therapy improved frailty, motor and cognitive function, and the senescent phenotype of the hippocampus compared with vehicle in SAMP10. In summary, SAMP10 showed more marked frailty characteristics than SAMR1, and dasatinib and quercetin attenuated them in SAMP10. From our results, senolytic therapy might contribute protective effects against frailty.
Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease. [2023]Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of Aβ42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and Aβ may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.
The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24 -/- Progeria Mouse Model. [2023]Aging leads to several geriatric conditions including osteoporosis (OP) and associated frailty syndrome. Treatments for these conditions are limited and none target fundamental drivers of pathology, and thus identifying strategies to delay progressive loss of tissue homeostasis and functional reserve will significantly improve quality of life in elderly individuals. A fundamental property of aging is the accumulation of senescent cells. Senescence is a cell state defined by loss of proliferative capacity, resistance to apoptosis, and the release of a proinflammatory and anti-regenerative senescence-associated secretory phenotype (SASP). The accumulation of senescent cells and SASP factors is thought to significantly contribute to systemic aging. Senolytics-compounds which selectively target and kill senescent cells-have been characterized to target and inhibit anti-apoptotic pathways that are upregulated during senescence, which can elicit apoptosis in senescent cells and relieve SASP production. Senescent cells have been linked to several age-related pathologies including bone density loss and osteoarthritis in mice. Previous studies in murine models of OP have demonstrated that targeting senescent cells pharmacologically with senolytic drugs can reduce symptomology of the disease. Here, we demonstrate the efficacy of senolytic drugs (dasatinib, quercetin, and fisetin) to improve age-associated degeneration in bone using the Zmpste24-/- (Z24-/-) progeria murine system for Hutchinson-Gilford progeria syndrome (HGPS). We found that the combination of dasatinib plus quercetin could not significantly mitigate trabecular bone loss although fisetin administration could reduce bone density loss in the accelerated aging Z24-/- model. Furthermore, the overt bone density loss observed in the Z24-/- model reported herein highlights the Z24 model as a translational model to recapitulate alterations in bone density associated with advanced age. Consistent with the "geroscience hypothesis," these data demonstrate the utility of targeting a fundamental driver of systemic aging (senescent cell accumulation) to alleviate a common condition with age, bone deterioration.
Fisetin is a senotherapeutic that extends health and lifespan. [2021]Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity.
Natural Products as a Major Source of Candidates for Potential Senolytic Compounds obtained by in silico Screening. [2023]Preclinical studies suggest that senolytic compounds such as quercetin (a natural product) and dasatinib (a synthetic product) decrease senescent cells, reduce inflammation, and alleviate human frailty. This evidence has opened a new field of research for studying the effect of these compounds on age-related dysfunction and diseases.
Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. [2023]Aging results in an elevated burden of senescent cells, senescence-associated secretory phenotype (SASP), and tissue infiltration of immune cells contributing to chronic low-grade inflammation and a host of age-related diseases. Recent evidence suggests that the clearance of senescent cells alleviates chronic inflammation and its associated dysfunction and diseases. However, the effect of this intervention on metabolic function in old age remains poorly understood. Here, we demonstrate that dasatinib and quercetin (D&Q) have senolytic effects, reducing age-related increase in senescence-associated β-galactosidase, expression of p16 and p21 gene and P16 protein in perigonadal white adipose tissue (pgWAT; all p ≤ 0.04). This treatment also suppressed age-related increase in the expression of a subset of pro-inflammatory SASP genes (mcp1, tnf-α, il-1α, il-1β, il-6, cxcl2, and cxcl10), crown-like structures, abundance of T cells and macrophages in pgWAT (all p ≤ 0.04). In the liver and skeletal muscle, we did not find a robust effect of D&Q on senescence and inflammatory SASP markers. Although we did not observe an age-related difference in glucose tolerance, D&Q treatment improved fasting blood glucose (p = 0.001) and glucose tolerance (p = 0.007) in old mice that was concomitant with lower hepatic gluconeogenesis. Additionally, D&Q improved insulin-stimulated suppression of plasma NEFAs (p = 0.01), reduced fed and fasted plasma triglycerides (both p ≤ 0.04), and improved systemic lipid tolerance (p = 0.006). Collectively, results from this study suggest that D&Q attenuates adipose tissue inflammation and improves systemic metabolic function in old age. These findings have implications for the development of therapeutic agents to combat metabolic dysfunction and diseases in old age.
Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial. [2023]Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility and efficacy. Five participants (mean age = 76 + 5 years; 40% female) completed the 12-week pilot study. D and Q levels in blood increased in all participants (12.7-73.5 ng ml-1 for D and 3.29-26.3 ng ml-1 for Q). In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) ranging from 0.281 to 0.536 ml-1 with a CSF to plasma ratio of 0.422-0.919%; Q was not detected. The treatment was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment further supporting a favorable safety profile. CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased (t(4) = 3.913, P = 0.008 and t(4) = 3.354, P = 0.028, respectively) with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ42 levels (t(4) = -2.338, P = 0.079). In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability and feasibility in patients with AD. Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies. ClinicalTrials.gov identifier: NCT04063124 .
Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. [2023]Dasatinib (Sprycel®) is a tyrosine kinase inhibitor for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.
[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. [2015]Dasatinib (Sprycel) is a new-targeted therapy used since 2005 in the treatment of chronic myelogenous leukemia and de novo Philadelphia positive acute lymphoblastic leukaemia patients, intolerant or resistant to imatinib. Despite its high efficacy in such patients in terms of hematologic, cytogenetic and molecular responses, the onset of frequent and sometimes serious side effects particularly in advanced phase patients, especially myelosuppressions and pleural effusions, may impair optimal administration of the drug. Recently, dasatinib dose optimisation in chronic-phase has reduced the incidence of such adverse events without modification of the efficacy, however, their optimal overall management can efficiently reduce their severity and minimize their impact on disease response. Hereby, we attempted to propose a series of guidelines that might be of help in daily practice, in order to control properly these side effects.
A validated LC-MS/MS assay for the simultaneous determination of the anti-leukemic agent dasatinib and two pharmacologically active metabolites in human plasma: application to a clinical pharmacokinetic study. [2015]Dasatinib (Sprycel) is a potent antitumor agent prescribed for patients with chronic myeloid leukemia (CML). To enable reliable quantification of dasatinib and its pharmacologically active metabolites in human plasma during clinical testing, a sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated. Samples were prepared using solid phase extraction on Oasis HLB 96-well plates. Chromatographic separation was achieved isocratically on a Luna phenyl-hexyl analytical column. Analytes and the stable labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The assay was validated over a concentration range of 1.00-1000 ng/mL for dasatinib and its two active metabolites. Intra- and inter-assay precision values for replicate QC control samples were within 5.3% for all analytes during the assay validation. Mean QC control accuracy values were within ± 9.0% of nominal values for all analytes. Assay recoveries were high (>79%) and internal standard normalized matrix effects were minimal. The three analytes were stable in human plasma for at least 22 h at room temperature, for at least 123 days at -20°C, and following at least six freeze-thaw cycles. The validated method was successfully applied to the quantification of dasatinib and two active metabolites in a human pharmacokinetic study.
Antidiabetic Effects of the Senolytic Agent Dasatinib. [2022]To evaluate the antidiabetic effects of the senolytic agent dasatinib in older patients with type 2 diabetes mellitus.
Metabolism and disposition of dasatinib after oral administration to humans. [2015]SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [(14)C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of