TGFβ signaling plays a key role in tumor progression, including malignant glioma. Small-molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGFβ signaling and reduce tumor progression ...in preclinical models. To use LY2157299 in the treatment of malignancies, we investigated its properties in a first-in-human dose (FHD) study in patients with cancer.
Sixty-five patients (58 with glioma) with measurable and progressive malignancies were enrolled. Oral LY2157299 was given as a split dose morning and evening on an intermittent schedule of 14 days on and 14 days off (28-day cycle). LY2157299 monotherapy was studied in dose escalation (part A) first and then evaluated in combination with standard doses of lomustine (part B). Safety was assessed using Common Terminology Criteria for Adverse Events version 3.0, echocardiography/Doppler imaging, serum troponin I, and brain natriuretic peptide (BNP) levels. Antitumor activity was assessed by RECIST and Macdonald criteria.
In part A, 16.6% (5/30) and in part B, 7.7% (2/26) of evaluable patients with glioma had either a complete (CR) or a partial response (PR). In both parts, 15 patients with glioma had stable disease (SD), 5 of whom had SD ≥ 6 cycles of treatment. Therefore, clinical benefit (CR+PR+SD ≥ 6 cycles) was observed in 12 of 56 patients with glioma (21.4%). LY2157299 was safe, with no cardiac adverse events.
On the basis of the safety, pharmacokinetics, and antitumor activity in patients with glioma, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation.
Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the ...subpopulation of GBM tumor-initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.
Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma Mellinghoff, Ingo K; van den Bent, Martin J; Blumenthal, Deborah T ...
The New England journal of medicine,
08/2023, Letnik:
389, Številka:
7
Journal Article
Recenzirano
Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 ...and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas.
In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed.
A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval CI, 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo.
In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).
This paper seeks to describe several features of the reverse logistics network design under extended producer responsibility, in which the collection goals and penalties for the management system are ...established by a regulatory legal framework. To address this design network challenge, the paper develops a mixed integer linear programming model for capacitated facility location, which meets recycling targets and minimize the cost of fines in case of infeasibility, through relaxation of constraints. Consequently, the optimal flows, the configuration of collection, reprocessing and recycling facilities, and the estimation of the monetary transfers necessary for the feasible operation of the optimal management system are computed. To illustrate the usefulness of the proposed model, a numerical example based on the case of out-of-use tires (OUT) in the Gran Santiago city of Chile is considered. Forty-two scenarios are defined by a specific offer of OUT for the year 2020 and a possible ratio of OUT to be collected in the reverse logistic network imposed by the authorities. The obtained results show the optimal sets of service center, collection centers and reprocessing plants for each scenario, allowing to study the maximum benefit/minimum investment to develop a management system under the EPR national law.
•Reverse logistics network design under extended producer responsibility is considered.•A mixed integer linear programming model for computing the optimal configuration of the network is developed.•The model meets recycling targets and minimize the cost of fines in case of infeasibility.•The case of out-of-use tires in the Gran Santiago city of Chile is studied.
Transforming growth factor-beta (TGF-β) signaling plays an important role in the fetal development of cardiovascular organs and in the repair mechanisms of the heart. Hence, inhibitors of the TGF-β ...signaling pathway require a careful identification of a safe therapeutic window and a comprehensive monitoring of the cardiovascular system. Seventy-nine cancer patients (67 glioma and 12 solid tumor) enrolled in a first-in-human dose study and received the TGF-β inhibitor LY2157299 monohydrate (LY2157299) as monotherapy (
n
= 53) or in combination with lomustine (
n
= 26). All patients were monitored using 2D echocardiography/color and Spectral Doppler (2D Echo with Doppler) every 2 months, monthly electrocardiograms, thorax computer tomography scans every 6 months, and monthly serum brain natriuretic peptide (BNP), troponin I, cystatin C, high-sensitivity C-reactive protein (hs-CRP). Administration of LY2157299 was not associated with medically relevant cardiovascular toxicities, including patients treated ≥6 months (
n
= 13). There were no increases of troponin I, BNP, or hs-CRP or reduction in cystatin C levels, which may have been considered as signs of cardiovascular injury. Blood pressure was generally stable during treatment. Imaging with echocardiography/Doppler showed an increase in mitral and tricuspid valve regurgitation by two grades of severity in only one patient with no concurrent clinical symptoms of cardiovascular injury. Overall, this comprehensive cardiovascular monitoring for the TGF-β inhibitor LY2157299 did not detect medically relevant cardiac toxicity and hence supports the evaluation of LY2157299 in future clinical trials.
Violations of the assumptions of complete information CI and independence of irrelevant alternatives (IIA) in discrete‐choice experiment (DCE) data imply sensitivity of preference estimates to the ...decision context and the alternatives evaluated. There is a paucity of evidence on how these two assumptions affect health‐preference results and whether the usual specifications of random‐parameters logit models are sufficient to address these violations. We assessed the appropriateness of these assumptions in a DCE valuating interventions to prevent long‐term health problems that could be identified through whole genome sequencing. A DCE survey was administered to members of a nationally representative consumer panel to elicit their preferences for options to reduce the risk of health problems. The treatment options presented (surgery, medication, and watchful waiting) and the context for the decisions elicited (severity and likelihood of the health problem) were varied experimentally to evaluate the sensitivity of preference results to such changes. We find evidence of IIA violations as the options presented to prevent health changed. Our results also are consistent with the expectation that additional substitutes decrease the monetized value of alternatives. We also find some evidence that the decision context can moderate such effects, which constitutes a new finding.
In the United States, more than 50% of kidneys in the lowest 15% quality range (those with Kidney Donor Profile Index >85) are discarded. Studies suggest that using more of these kidneys could ...benefit patients waiting for a transplant. This study assesses the trade-offs physicians make when selecting recipients for lower-quality kidneys.
A discrete choice experiment (DCE) was administered to surgeons and nephrologists in the United States who are involved in kidney acceptance decisions. The DCE presented kidneys that varied in terms of Kidney Donor Profile Index, expected cold ischemia time, donor age, pump parameters, serum creatinine levels, glomerulosclerosis, donor diabetes status, and whether donation was made after circulatory death. Candidate characteristics included recipients' age, diabetes history, time on dialysis, ejection fraction, HLA mismatch, calculated panel reactive antibody, and Karnofsky performance score. Regression analysis was used to estimate acceptability weights associated with kidney and recipient characteristics.
A total of 108 physicians completed the DCE. The likelihood of acceptance was significantly lower with deterioration of kidney quality, expected cold ischemia time at transplantation, and missing biopsy and pump information. Acceptance was prioritized for patients who were higher on the waiting list, younger recipients, those who have spent less time on dialysis, and those without a history of diabetes. Performance status (Karnofsky score) and calculated panel reactive antibody also had a statistically significant but smaller association. Finally, ejection fraction had a marginally significant association, and HLA match had no significant association with the acceptance of marginal kidneys. A group of respondents were found to be primarily concerned about cold ischemia time.
In this DCE, physicians considered the recipient characteristics that inform expected post-transplant survival score when they decided whether to accept a marginal kidney for a given recipient.
Summary
Purpose
Transforming growth factor-beta (TGF-β) signaling plays a key role in epithelial-mesenchymal transition (EMT) of tumors, including malignant glioma. Small molecule inhibitors (SMI) ...blocking TGF-β signaling reverse EMT and arrest tumor progression. Several SMIs were developed, but currently only LY2157299 monohydrate (galunisertib) was advanced to clinical investigation.
Design
The first-in-human dose study had three parts (Part A, dose escalation,
n
= 39; Part B, safety combination with lomustine,
n
= 26; Part C, relative bioavailability study,
n
= 14).
Results
A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted a therapeutic window up to 300 mg/day and was confirmed in Part A after continuous PK/PD. PK was not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes in pSMAD2 levels in peripheral blood mononuclear cells were associated with exposure indicating target-related pharmacological activity of galunisertib. Twelve (12/79; 15 %) patients with refractory/relapsed malignant glioma had durable stable disease (SD) for 6 or more cycles, partial responses (PR), or complete responses (CR). These patients with clinical benefit had high plasma baseline levels of MDC/CCL22 and low protein expression of pSMAD2 in their tumors. Of the 5 patients with IDH1/2 mutation, 4 patients had a clinical benefit as defined by CR/PR and SD ≥6 cycles. Galunisertib had a favorable toxicity profile and no cardiac adverse events.
Conclusion
Based on the PK, PD, and biomarker evaluations, the intermittent administration of galunisertib at 300 mg/day is safe for future clinical investigation.
The combination of galunisertib, a transforming growth factor (TGF)-β receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma.
Galunisertib ...(300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity.
One hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of ∼8 hours. Median OS in months (95% credible interval CrI) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine P (HR < 1) = 26%. Median progression-free survival of ∼2 months was observed in all 3 arms. Among 8 patients with IDH1 mutation, 7 patients were treated with galunisertib (monotherapy or with lomustine); OS ranged from 4 to 17 months. Patients treated with galunisertib alone had fewer drug-related grade 3/4 adverse events (n = 34) compared with lomustine-treated patients (10% vs 26%). Baseline PS, post-discontinuation of bevacizumab, tumor size, and baseline levels of MDC/CCL22 were correlated with OS.
Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms.
NCT01582269, ClinicalTrials.gov.
Black carbon (BC) from fossil fuel and biomass combustion darkens the snow and makes it melt sooner. The BC footprint of research activities and tourism in Antarctica has likely increased as human ...presence in the continent has surged in recent decades. Here, we report on measurements of the BC concentration in snow samples from 28 sites across a transect of about 2,000 km from the northern tip of Antarctica (62°S) to the southern Ellsworth Mountains (79°S). Our surveys show that BC content in snow surrounding research facilities and popular shore tourist-landing sites is considerably above background levels measured elsewhere in the continent. The resulting radiative forcing is accelerating snow melting and shrinking the snowpack on BC-impacted areas on the Antarctic Peninsula and associated archipelagos by up to 23 mm water equivalent (w.e.) every summer.
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