Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

Background: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed.

Methods: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group).

Reversal of Solvent Migration in Poroelastic Folds.

Polymer networks and biological tissues are often swollen by a solvent such that their properties emerge from a coupling between swelling and elastic stress. This poroelastic coupling becomes particularly intricate in wetting, adhesion, and creasing, for which sharp folds appear that can even lead to phase separation. Here, we resolve the singular nature of poroelastic surface folds and determine the solvent distribution in the vicinity of the fold tip.

Smartphone and Wearable Sensors for the Estimation of Facioscapulohumeral Muscular Dystrophy Disease Severity: Cross-sectional Study.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disease. Its slow and variable progression makes the development of new treatments highly dependent on validated biomarkers that can quantify disease progression and response to drug interventions.

Objective: We aimed to build a tool that estimates FSHD clinical severity based on behavioral features captured using smartphone and remote sensor data.

A Placebo-Controlled Study to Assess the Sensitivity of Finger Tapping to Medication Effects in Parkinson's Disease.

Background: Movement Disorder Society-Unified Parkinson's Rating Scale Part III (MDS-UPDRS III) is the gold standard for assessing medication effects in patients with Parkinson's disease (PD). However, short and rater-independent measurements would be ideal for future trials.

Objectives: To assess the ability of 3 different finger tapping tasks to detect levodopa/carbidopa-induced changes over time and to determine their correlation and compare their discriminatory power with MDS-UPDRS III.

Integration of healthy volunteers in early phase clinical trials with immuno-oncological compounds.

Aim: Traditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials.

Objective Monitoring of Facioscapulohumeral Dystrophy During Clinical Trials Using a Smartphone App and Wearables: Observational Study.

Background: Facioscapulohumeral dystrophy (FSHD) is a progressive muscle dystrophy disorder leading to significant disability. Currently, FSHD symptom severity is assessed by clinical assessments such as the FSHD clinical score and the Timed Up-and-Go test. These assessments are limited in their ability to capture changes continuously and the full impact of the disease on patients' quality of life.

Soft wetting with (a)symmetric Shuttleworth effect.

The wetting of soft polymer substrates brings in multiple complexities when compared with the wetting on rigid substrates. The contact angle of the liquid is no longer governed by Young's Law, but is affected by the substrate's bulk and surface deformations. On top of that, elastic interfaces exhibit a surface energy that depends on how much they are stretched-a feature known as the Shuttleworth effect (or as surface-elasticity).

A Randomized First-in-Human Study With UB-312, a UBITh® α-Synuclein Peptide Vaccine.

Background: α-Synuclein (αSyn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic αSyn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar αSyn, making UB-312 a potential immunotherapeutic for synucleopathies.

Objective: To investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study.

Safety and pharmacokinetics of multiple dosing with inhalable apomorphine (AZ-009), and its efficacy in a randomized crossover study in Parkinson's disease patients.

Introduction: Apomorphine is used to treat OFF periods in Parkinson's disease (PD) patients. AZ-009 is a novel apomorphine formulation that delivers a thermally-generated aerosol to the deep lung via inhalation with a single breath.

Methods: Part A was a randomized, placebo-controlled, double-blind study investigating the safety and pharmacokinetics of multiple ascending doses of AZ-009.

A Randomized Trial Assessing the Safety, Pharmacokinetics, and Efficacy During Morning Off of AZ-009.

Background: Inhalation of apomorphine could be a faster-acting and more user-friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD).

Objective: The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ-009) with subcutaneous apomorphine (APO-go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ-009 in patients with PD.

Methods: In part A of this study, eight HVs received 1 mg AZ-009 and 2 mg subcutaneous apomorphine in a randomized crossover manner.

A phase I, randomized, double-blind, placebo-controlled, single- and multiple dose escalation study evaluating the safety, pharmacokinetics and pharmacodynamics of VX-128, a highly selective Na 1.8 inhibitor, in healthy adults.

Selective inhibition of certain voltage-gated sodium channels (Na s), such as Na 1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX-128 is a highly potent and selective Na 1.

Touchscreen-based finger tapping: Repeatability and configuration effects on tapping performance.

Parkinson's disease (PD) is a progressive neurodegenerative disease that affects almost 2% of the population above the age of 65. To better quantify the effects of new medications, fast and objective methods are needed. Touchscreen-based tapping tasks are simple yet effective tools for quantifying drug effects on PD-related motor symptoms, especially bradykinesia.

Healthy volunteers in first-in-human oncology drug development for small molecules.

This review provides tools to consider the inclusion of healthy volunteers (HVs) in first-in-human (FIH) oncology clinical trials with small molecules, including targeted and immunomodulatory agents, a strategy that was not envisioned with classic chemotherapy. To enable an FIH oncology trial in HVs compared to cancer patients (CPs), a robust nonclinical package must be generated, which includes toxicokinetic and pharmacokinetic studies, as well as more extensive safety pharmacology, toxicology and genotoxicity studies. This strategy could provide an early clinical characterization of the pharmacokinetic parameters and clinical safety profile in the absence of comorbidities and concomitant medication.

First-in-human trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324, a dual enkephalinase inhibitor for pain management.

Aim: Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324 in healthy male participants.

Phase 1 clinical trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, pharmacokinetics, and target engagement.

Aims: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).

Methods: This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.

Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer.

Lessons Learned: Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.

First-in-human administration of a live-attenuated RSV vaccine lacking the G-protein assessing safety, tolerability, shedding and immunogenicity: a randomized controlled trial.

Background: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early infancy and in elderly. A pediatric vaccine against RSV would not only prevent morbidity and mortality amongst infants and young children but could also reduce transmission to elderly. The RSVΔG vaccine consists of a live-attenuated RSV that lacks the G attachment protein.

Quantification of tremor using consumer product accelerometry is feasible in patients with essential tremor and Parkinson's disease: a comparative study.

Background: To quantify pharmacological effects on tremor in patients with essential tremor (ET) or Parkinson's Disease (PD), laboratory-grade accelerometers have previously been used. Over the last years, consumer products such as smartphones and smartwatches have been increasingly applied to measure tremor in an easy way. However, it is unknown how the technical performance of these consumer product accelerometers (CPAs) compares to laboratory-grade accelerometers (LGA).

Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer.

Purpose: KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R).

Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer.

Background: Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g.

Prevalent levels of RSV serum neutralizing antibodies in healthy adults outside the RSV-season.

One of the main challenges in early clinical research with respiratory syncytial virus (RSV) live-attenuated vaccines (LAVs) is to assess immunogenicity in healthy adults. Healthy adults will have preexisting levels of serum neutralizing antibodies that could prematurely neutralize the LAV and underestimate the potential effect of the vaccine on the immune system. Data on prevalence and distribution of virus neutralizing titers (VNTs) in healthy adults is limited and there is no absolute threshold for protection against RSV-infection that can serve as an eligibility criterion in early phase trials.

A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma.

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma.

T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.

Purpose: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.

Methods: KEYNOTE-028 ( ClinicalTrials.