Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance.

Background: In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance + best supportive care (BSC) prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (advanced UC) without progression after first-line platinum-based chemotherapy.

Objective: To report post hoc analyses of subgroups defined by the duration of first-line chemotherapy and interval before maintenance.

Design, Setting, And Participants: Patients with advanced UC without progression after four to six cycles of platinum-based chemotherapy and a 4-10-wk interval after chemotherapy (n = 700) were randomized to receive avelumab + BSC or BSC alone.

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial.

Background: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC).

Patients And Methods: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.

Avelumab First-line Maintenance Therapy for Advanced Urothelial Carcinoma: Comprehensive Clinical Subgroup Analyses from the JAVELIN Bladder 100 Phase 3 Trial.

Background: In the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free following 1L platinum-based chemotherapy, leading to regulatory approval in various countries.

Objective: To analyze clinically relevant subgroups from JAVELIN Bladder 100.

Design, Setting, And Participants: Patients with unresectable locally advanced or metastatic UC without progression on 1L gemcitabine + cisplatin or carboplatin were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350).

Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up.

JCO Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC.

Plain language summary of results from the JAVELIN Bladder 100 study: avelumab maintenance treatment for advanced urothelial cancer.

What Is This Summary About?: This is a plain language summary of an article originally published in . It is about initial results (collected in October 2019) from the JAVELIN Bladder 100 study (a clinical trial), which looked at avelumab maintenance treatment in people with advanced urothelial cancer. Urothelial cancer is the most common type of bladder cancer.

Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma.

Background: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.

Methods: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab.

Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors.

Purpose: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks.

Bumps in the journey toward a new care delivery model.

On a journey to the future, an initial strategy of engagement and design is essential but inevitably inadequate. Instead, as bumps in the road emerge, the ability of leadership to regroup and refocus is the key. This is the story of one such journey-a journey pursuing the triple aim of excellence in patient care, patient and staff satisfaction, and economic sustainability.

CDX-1307: a novel vaccine under study as treatment for muscle-invasive bladder cancer.

Cancer vaccines have demonstrated clinical benefit, however greater efficacy could be achieved by enhancing their immunogenicity. Owing to cancer vaccines depending on uptake and cross-presentation of tumor antigens by antigen-presenting cells (APCs), we hypothesized that greater immunogenicity would accompany strategies that direct antigen to APC-expressed mannose receptors, initiating a pathway increasing class I and II presentation to T cells. CDX-1307 consists of a human monoclonal antibody targeting the mannose receptor, fused to the human chorionic gonadotropin-β chain (hCG-β), a tumor antigen frequently expressed by epithelial cancers including bladder cancer.

A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides.

Background: Interleukin-12 (IL-12) increases Th(1) cytokines, natural killer (NK) cells, and cytotoxic T-cell activities. Progression of mycosis fungoides is associated with Th(2) cytokines produced by a clonal proliferation of epidermotropic T-helper cells.

Objective: To determine the safety and efficacy of subcutaneous recombinant human IL-12 (rhIL-12) in early mycosis fungoides (MF; stage IA-IIA) in a multi-center, open label clinical trial.

Structure-activity relationships of triazolopyridine oxazole p38 inhibitors: identification of candidates for clinical development.

The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.

Phase 1 study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder.

Superficial transitional cell carcinoma (STCC) of the bladder is usually managed with intravesical bacille Calmette-Guerin. Recombinant human interleukin-12 (rhIL-12) is a heterodimeric cytokine that induces T-cell and natural killer cell proliferation/activation and production of IFNgamma. It has demonstrated preclinical in vivo bladder antitumor activity and no systemic toxicity.

Glutathione s-transferase omega 1-1 is a target of cytokine release inhibitory drugs and may be responsible for their effect on interleukin-1beta posttranslational processing.

Stimulus-induced posttranslational processing of human monocyte interleukin-1beta (IL-1beta) is accompanied by major changes to the intracellular ionic environment, activation of caspase-1, and cell death. Certain diarylsulfonylureas inhibit this response, and are designated cytokine release inhibitory drugs (CRIDs). CRIDs arrest activated monocytes so that caspase-1 remains inactive and plasma membrane latency is preserved.

The role for interleukin-12 therapy of cutaneous T cell lymphoma.

Recent phase I and phase II trials using recombinant human interleukin-12 (rhIL-12) for cutaneous T cell lymphoma (CTCL) have been completed. Observations on 32 evaluable patients revealed an overall response rate approaching 50 percent. Biopsy of regressing lesions revealed an increase in numbers of CD8+ and/or TIA-1+ T cells.

Identification and characterization of a novel class of interleukin-1 post-translational processing inhibitors.

Lipopolysaccharide (LPS)-activated monocytes and macrophages produce large quantities of pro-interleukin (IL)-1beta but externalize little mature cytokine. Efficient post-translational processing of the procytokine occurs in vitro when these cells encounter a secretion stimulus such as ATP, cytolytic T cells, or hypotonic stress. Each of these stimuli promotes rapid conversion of 31-kDa pro-IL-1beta to its mature 17-kDa species and release of the 17-kDa cytokine.

Decreased capacity of asthmatic bronchial fibroblasts to degrade collagen.

The mechanisms of fibrillar collagen accumulation in asthmatic bronchi remain unclear, an imbalance between synthesis and degradation of collagen may be implicated in this process. The aim of this study was to compare the capacities of normal (BNF) and asthmatic (BAF) bronchial fibroblasts to degrade collagen. Metalloproteinases and their inhibitors were measured by ELISA, types I and III procollagen synthesis was determined by liquid RIA and, finally, zymography was used to assess the presence of active and latent forms of MMPs.

ATP acts as an agonist to promote stimulus-induced secretion of IL-1 beta and IL-18 in human blood.

Cultured monocytes and macrophages stimulated with LPS produce large quantities of proIL-1beta, but release little mature cytokine to the medium. The efficiency at which the procytokine is converted to its active 17-kDa species and released extracellularly is enhanced by treating cytokine-producing cells with a secretion stimulus such as ATP or nigericin. To determine whether this need for a secretion stimulus extends to blood, individual donors were bled twice daily for 4 consecutive days, and the collected blood samples were subjected to a two-step IL-1 production assay.

ATP treatment of human monocytes promotes caspase-1 maturation and externalization.

Mechanisms that regulate conversion of prointerleukin-1beta (pro-IL-1beta) to its mature form by the cysteine protease caspase-1 are not well understood. In this study, we demonstrate that mature caspase-1 subunits are produced when human monocytes are treated with ATP and, like mature IL-1beta, are released extracellularly. Characterization of the pharmacological sensitivity of this stimulus-coupled response revealed that some caspase-1 inhibitors allow pro-IL-1beta secretion, whereas others do not.

Human monocyte ATP-induced IL-1 beta posttranslational processing is a dynamic process dependent on in vitro growth conditions.

Despite a large production capacity, freshly isolated lipopolysaccharide (LPS)-activated human monocytes release only a small percentage of their newly synthesized interleukin (IL)-1 beta into the medium. Extracellular ATP, acting via surface P2z-type purino-receptors, increases cytokine posttranslational processing. To explore whether this ATP response was affected by culture conditions, monocytes were maintained for different time periods in the absence and presence of various media components including fetal bovine and human sera and recombinant human cytokines.

Human monocyte interleukin-1beta posttranslational processing. Evidence of a volume-regulated response.

Interleukin (IL)-1beta produced by monocytes and macrophages is not released via the normal secretory apparatus, and prior to its release, this cytokine must be proteolytically processed to generate a mature biologically active species. Biochemical mechanisms that regulate these posttranslational steps are not well understood. Lipopolysaccharide (LPS) is a poor activator of IL-1 posttranslational processing despite serving as a potent inducer of IL-1 synthesis.

Lower airways remodeling in nonasthmatic subjects with allergic rhinitis.

We analyzed by immunohistochemistry the distribution of types I, II, III, IV, V, and VII collagens, laminin, and fibronectin in the bronchial biopsy specimens of nonasthmatic subjects with seasonal allergic rhinitis (n = 8) and compared these results with those found in mild stable allergic asthmatics (n = 6) and normal controls (n = 5). The content of type I and III collagens was increased in rhinitic subjects compared with controls. These collagens were focally deposited in the reticular basement membrane area.

Inhibition of cytokine activation processes in vitro by tenidap, a novel anti-inflammatory agent.

Tenidap is a novel anti-inflammatory and anti-arthritic agent that lowers intracellular pH and suppresses anion transport when applied to cells in vitro. Both of these parameters are known to influence pro-inflammatory cell function. To investigate whether tenidap can modulate cellular responses to cytokine stimulation, several in vitro cytokine-driven assays were characterized with respect to their tenidap sensitivity.

Tenidap modulates cytoplasmic pH and inhibits anion transport in vitro. II. Inhibition of IL-1 beta production from ATP-treated monocytes and macrophages.

IL-1 beta is an important inflammatory mediator produced by monocytes and macrophages after LPS stimulation. In the absence of a secondary stimulus, however, little IL-1 beta is released into the medium. Previously, ATP was shown to promote the release and proteolytic maturation of IL-1 beta from LPS-stimulated murine peritoneal macrophages.

Effect of mitochondrial viability and metabolism on technetium-99m-sestamibi myocardial retention.

This study investigated the mechanism of myocardial retention of technetium-99m-sestamibi. 99mTc-sestamibi was injected intravenously into guinea pigs, and the myocardium was homogenized and fractionated by differential centrifugation. More than 90% of myocardial 99mTc-sestamibi was localized within the mitochondrial fraction.