Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor

CLR457; Inhibidor Pan-PI3K; Fase ICLR457; Inhibidor Pan-PI3K; Fase ICLR457; Pan-PI3K inhibitor; Phase IBackground CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110β, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities—51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.Novartis Pharmaceuticals Corporation

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

[Excerpt] Multiple myeloma (MM) is the third most common hematological malignancy, after Non-Hodgkin Lymphoma and Leukemia. MM is generally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS) [1], and epidemiological studies have identified older age, male gender, family history, and MGUS as risk factors for developing MM [2]. The somatic mutational landscape of sporadic MM has been increasingly investigated, aiming to identify recurrent genetic events involved in myelomagenesis. Whole exome and whole genome sequencing studies have shown that MM is a genetically heterogeneous disease that evolves through accumulation of both clonal and subclonal driver mutations [3] and identified recurrently somatically mutated genes, including KRAS, NRAS, FAM46C, TP53, DIS3, BRAF, TRAF3, CYLD, RB1 and PRDM1 [3,4,5]. Despite the fact that family-based studies have provided data consistent with an inherited genetic susceptibility to MM compatible with Mendelian transmission [6], the molecular basis of inherited MM predisposition is only partly understood. Genome-Wide Association (GWAS) studies have identified and validated 23 loci significantly associated with an increased risk of developing MM that explain ~16% of heritability [7] and only a subset of familial cases are thought to have a polygenic background [8]. Recent studies have identified rare germline variants predisposing to MM in KDM1A [9], ARID1A and USP45 [10], and the implementation of next-generation sequencing technology will allow the characterization of more such rare variants. [...]French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organizatio

First-in-human, dose-escalation, phase 1 study of anti-angiopoietin-2 LY3127804 as monotherapy and in combination with ramucirumab in patients with advanced solid tumours

Desenvolupament de fàrmacsDesarrollo de fármacosDrug developmentBackground This is the first-in-human study of novel anti-angiopoietin-2 (Ang-2) monoclonal antibody LY3127804 as monotherapy and in combination with ramucirumab in advanced solid tumours. Methods Patients received intravenous LY3127804 monotherapy (4, 8, 12, 16, 20 and 27 mg/kg) in part A; LY3127804 (8, 12, 16, 20 and 27 mg/kg) with 8 mg/kg ramucirumab in part B; and LY3127804 (20 mg/kg) with 12 mg/kg ramucirumab in part C. Treatments were administered every 2 weeks (Q2W) during 28-day cycles. Dose-escalation was based on cycle 1 dose-limiting toxicities (DLTs). Results Sixty-two patients were treated in part A (n = 20), part B (n = 35) and part C (n = 7). Constipation, diarrhoea and fatigue were the most common treatment-emergent adverse events (TEAEs) in part A; hypertension and peripheral oedema were the most frequent TEAE in parts B and C. No DLT was observed and maximum tolerated dose for LY3127804 was not reached. Four patients achieved partial response with combination therapy (clear cell endometrial carcinoma, cervix squamous cell carcinoma, carcinoma of unknown primary and gastroesophageal junction carcinoma), 29 achieved stable disease, and 24 had progressive disease. Conclusions LY3127804 monotherapy and its combination with ramucirumab are well tolerated. LY3127804 20 mg/kg was the recommended Phase 2 dose.The trial was sponsored by Eli Lilly and Company

Localized Supramolecular Peptide Self-Assembly Directed by Enzyme-Induced Proton Gradients

International audienceElectrodes are ideal substrates for surface localized self-assembly processes. Spatiotemporal control over such processes is generally directed through the release of ions generated by redox reactions occurring specifically at the electrode. The so-used gradients of ions proved their effectiveness over the last decade but are in essence limited to material-based electrodes, considerably reducing the scope of applications. Herein is described a strategy to enzymatically generate proton gradients from non-conductive surfaces. In the presence of oxygen, immobilization of glucose oxidase (GOx) on a multilayer film provides a flow of protons through enzymatic oxidation of glucose by GOx. The confined acidic environment located at the solid-liquid interface allows the self-assembly of Fmoc-AA-OH (Fmoc=fluorenylmethyloxycarbonyl and A=alanine) dipeptides into β-sheet nanofibers exclusively from and near the surface. In the absence of oxygen, a multilayer nanoreactor containing GOx and horseradish peroxidase (HRP) similarly induces Fmoc-AA-OH self-assembly