Remote Monitoring and Data Collection for Decentralized Clinical Trials.

Importance: Less than 5% of patients with cancer enroll in a clinical trial, partly due to financial and logistic burdens, especially among underserved populations. The COVID-19 pandemic marked a substantial shift in the adoption of decentralized trial operations by pharmaceutical companies.

Objective: To assess the current global state of adoption of decentralized trial technologies, understand factors that may be driving or preventing adoption, and highlight aspirations and direction for industry to enable more patient-centric trials.

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis.

Background: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy.

Methods: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy.

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.

Background: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.

Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months.

Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials.

Aim: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival.

Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.

Background: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients.

Patients And Methods: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma.

Pyrexia in dabrafenib-treated melanoma patients is not associated with common genetic variation or HLA polymorphisms.

Aim: Pyrexia is a common adverse event (AE) on dabrafenib treatment (monotherapy or combination with trametinib). Since germline SNPs and HLA alleles are implicated in drug-induced AEs, this study investigated their association with pyrexia.

Patients & Methods: 1006 melanoma subjects from five dabrafenib-trametinib clinical studies underwent genotyping for genome-wide SNPs, which enabled imputation of 150 HLA alleles.

Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials.

Purpose: Tumor-derived circulating cell-free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome.

Experimental Design: Patients with BRAF V600 mutation-positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay.

Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial.

Background: In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study.

Methods: COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy.

Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.

Background: Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article.

Methods: We did this double-blind phase 3 study at 113 sites in 14 countries.

Improved overall survival in melanoma with combined dabrafenib and trametinib.

Background: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients.

Methods: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy.

BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency.

Purpose: An intact immune system likely contributes to the outcome of treatment and may be important for clearance of drug-resistant tumor cells and for prevention of recurrence. Although pharmacologic inhibition of BRAF(V600E) in melanoma patients, which is linked to immune suppression, results in an initial response rate, these responses are typically of limited duration. Combining immunotherapeutic drugs with kinase-targeted agents is an attractive strategy to increase clinical efficacy.

Selective CETP inhibition and PPARalpha agonism increase HDL cholesterol and reduce LDL cholesterol in human ApoB100/human CETP transgenic mice.

Cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) cholesterol metabolism, but normal mice are deficient in CETP. In this study, transgenic mice expressing both human apolipoprotein B 100 (ApoB-100) and human CETP (hApoB100/hCETP) were used to characterize the effects of CETP inhibition and peroxisome proliferator-activated receptor alpha (PPARalpha) agonism on lipid profiles. Torcetrapib (3, 10, and 30 mg/kg), a CETP inhibitor, fenofibrate (30 mg/kg), a weak PPARalpha agonist, and GW590735 (3 and 10 mg/kg), a potent and selective PPARalpha agonist were given orally for 14 days to hApoB100/hCETP mice and lipid profiles were assessed.

SB 234551 selective ET(A) receptor antagonism: perfusion/diffusion MRI used to define treatable stroke model, time to treatment and mechanism of protection.

Mismatches between tissue perfusion-weighted imaging (PWI; an index of blood flow deficit) and cellular diffusion-weighted imaging (DWI; an index of tissue injury) provide information on potentially salvageable penumbra tissue in focal stroke and can identify "treatable" stroke patients. The present pre-clinical studies were conducted to: a.) Determine PWI (using perfusion delay) and DWI measurements in two experimental stroke models, b.

Inhibition of phosphodiesterase type 4 decreases stress-induced defecation in rats and mice.

Background/aims: Phosphodiesterase type 4 (PDE4) has been previously shown to regulate colonic contractile activity in vitro. In this study, the effects of PDE4 inhibition were assessed in a model of stress-induced defecation previously demonstrated to be due to increased colonic transit/evacuation.

Methods: Rats were individually placed in a mild restraint cage and placed into a 12 degrees C environment (cold-restraint stress) for 60 min.

Selective PPARdelta agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study.

Peroxisome proliferator-activated receptor-delta (PPARdelta) activation results in upregulation of genes associated with skeletal muscle fatty acid oxidation and mitochondrial uncoupling. However, direct, noninvasive assessment of lipid metabolism and mitochondrial energy coupling in skeletal muscle following PPARdelta stimulation has not been examined. Therefore, in this study we examined the response of a selective PPARdelta agonist (GW610742X at 5 or 100 mg.

Caspase inhibitors as neuroprotective agents.

Apoptotic neuronal cell death has been demonstrated to occur in the central nervous system (CNS), following both acute injury and during chronic neurodegenerative conditions. Currently, the majority of experimental evidence for a role of caspases in CNS damage has been established following acute neuronal insults, including ischaemic stroke, traumatic brain injury and spinal cord injury. In vitro and in vivo models have been used to demonstrate caspase activation, and treatment with available caspase inhibitors can provide significant protection.

Update on pharmacological strategies for stroke: prevention, acute intervention and regeneration.

Given the few options that are currently available for patients following ischemic stroke, the search for novel therapeutic approaches becomes more critical. Pharmaceutical intervention strategies for the treatment of stroke include preventative (prophylactic or stroke pretreatment), neuroprotective (early acute post-stroke treatment) and regenerative (delayed post-stroke treatment for long-term benefit) therapeutic approaches. Experimental evidence has suggested that the majority of stroke patients have a slow evolution of brain injury that occurs over several hours.

Caspase 3 activation is essential for neuroprotection in preconditioning.

Sublethal insults can induce tolerance to subsequent stressors in neurons. As cell death activators such as ROS generation and decreased ATP can initiate tolerance, we tested whether other cellular elements normally associated with neuronal injury could add to this process. In an in vivo model of ischemic tolerance, we were surprised to observe widespread caspase 3 cleavage, without cell death, in preconditioned tissue.

The selective p38 inhibitor SB-239063 protects primary neurons from mild to moderate excitotoxic injury.

Inhibition of the p38 mitogen-activated protein kinase (MAP Kinase) pathway reduces acute ischemic injury in vivo, suggesting a direct role for this signaling pathway in a number of neurodegenerative processes. The present study was designed to evaluate further the role of p38 MAP Kinase in acute excitotoxic neuronal injury using the selective p38 inhibitor SB-239063 (trans-1-(4hydroxycyclohexyl)-4-(fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl) imidazole). Unlike the widely used p38 inhibitor, SB-203580 (4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole), this second generation p38 inhibitor more selectively inhibits p38 MAP Kinase without affecting the activity of other MAP Kinase signaling pathways and provides a more accurate means to selectively assess the role of p38 in excitotoxicity that has not been previously possible.

Pharmacological interventions for stroke: failures and future.

Given the few options currently available for patients following ischaemic stroke, the recent disappointing failures of several large-scale Phase III clinical trials has made the search for novel therapeutic approaches even more critical. Experimental evidence has suggested that the majority of stroke patients have a slow evolution of brain injury which can occur over several hours. Progressive microcirculatory failure following the initial onset of ischaemia may contribute to the expansion of brain injury.

LEX032, a novel recombinant serpin, protects the brain after transient focal ischemia.

This investigation examined the effectiveness of a serine protease inhibitor (LEX032) when used as a cerebral protective agent after ischemia. Focal cerebral ischemia in the rat was produced by intravascular occlusion of the middle cerebral artery for a period of 30 min. Just prior to thread withdrawal (i.

Non-surgical management of spinal cord injury.

Spinal cord injury remains a devastating neurological condition with limited therapeutic opportunities. Since decompressive surgery and high-dose methylprednisolone have limited utility for most patients, spinal cord injury clearly represents a major medical challenge. Experimental evidence has suggested that secondary cellular injury processes may be a realistic target for therapeutic intervention with the goal of inhibiting the progression of detrimental changes that normally follows traumatic injury to the cord.

Coadministration of methylprednisolone with hypertonic saline solution improves overall neurological function and survival rates in a chronic model of spinal cord injury.

Objective: We previously demonstrated that administration of 7.5% hypertonic saline (HS) significantly improved spinal cord blood flow and neurological outcomes after spinal cord injury. The aim of this study was to determine whether hypertonicity would enhance the effects of methylprednisolone (MP), further improving neurological function.