A5003079347- Monoclonal and Polyclonal Antibodies Research
- Lymphoma Diagnosis and Treatment
- Chronic Lymphocytic Leukemia Research
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Biosimilars and Bioanalytical Methods
- HIV/AIDS drug development and treatment
- Acute Myeloid Leukemia Research
- Lung Cancer Treatments and Mutations
- Vasculitis and related conditions
- HIV Research and Treatment
- Statistical Methods in Clinical Trials
- Cancer Genomics and Diagnostics
- Computational Drug Discovery Methods
- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Cancer Treatment and Pharmacology
- DNA Repair Mechanisms
- Acute Lymphoblastic Leukemia research
- Viral-associated cancers and disorders
- Renal Diseases and Glomerulopathies
- Cholinesterase and Neurodegenerative Diseases
- Renal Transplantation Outcomes and Treatments
- Inflammasome and immune disorders
- Hemoglobinopathies and Related Disorders
Roche (Switzerland)
2014-2024
Université Paris-Saclay
2004
Hôpital Paul-Brousse
2004
The phase III MIRROS trial (NCT02545283) evaluated the efficacy and safety of small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Adults (N=447) R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment following salvage chemotherapy regimen, Eastern Cooperative Oncology Group performance status were enrolled regardless TP53 mutation randomly assigned 2:1 to 300 mg...
Abstract Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation -expansion studies: single agent with or without obinutuzumab S1 (NCT02324257) atezolizumab S2 (NCT02650713). Primary endpoints were safety, dose finding, pharmacokinetics S1; safety finding S2. Secondary anti-tumour...
Effective T-cell responses not only require the engagement of receptors (TCRs; "signal 1"), but also availability costimulatory signals ("signal 2"). bispecific antibodies (TCBs) deliver a robust signal 1 by engaging TCR signaling component CD3ε, while simultaneously binding to tumor antigens. The CD20-TCB glofitamab redirects T cells CD20-expressing malignant B cells. Although exhibits strong single-agent efficacy, adding may enhance depth and durability T-cell-mediated cell killing. We...
Treatment regimens involving obinutuzumab (GA101) demonstrated increased efficacy to rituximab in clinical trials for non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). However, the pharmacokinetic (PK) properties exposure-response relationships of still need be fully described. Data from four were analyzed describe PK patients with NHL or CLL pharmacodynamic (PD) CLL. A population model linear time-dependent clearance described concentration-time course. Diagnosis,...
The limited effectiveness of rituximab plus intravenous immunoglobulin (IVIG) in desensitization may be due to incomplete B cell depletion. Obinutuzumab is a type 2 anti-CD20 antibody that induces increased depletion relative and therefore more effective for desensitization. This open-label phase 1b study assessed the safety, pharmacokinetics, pharmacodynamics obinutuzumab highly sensitized patients with end-stage renal disease. Patients received 1 (day 1, n = 5) or (days 15; 20) infusions...
Existing survival prediction models rely only on baseline or tumor kinetics data and lack machine learning integration. We introduce a novel kinetics‐machine (kML) model that integrates markers, kinetics, four on‐treatment simple blood markers (albumin, C‐reactive protein, lactate dehydrogenase, neutrophils). Developed for immune‐checkpoint inhibition (ICI) in non‐small cell lung cancer three phase II trials (533 patients), kML was validated the two arms of III trial (ICI chemotherapy, 377...
Objectives: Model development recommendations encompass a series of building steps and procedures that have been proven to be effective thus desirable closely followed. Well-established pharmacometrics (PMx) beneficial in formalizing modeling simulation tasks toward informed decision-making regulatory submission. In recent years, machine learning (ML) methods gained popularity the PMx community because their potential decipher relationships between patient characteristics predict individual...
Inclacumab, a novel monoclonal antibody against P-selectin in development for the treatment and prevention of atherosclerotic cardiovascular diseases, was administered an ascending single-dose study as intravenous infusion to evaluate safety, pharmacokinetics, pharmacodynamics. Fifty-six healthy subjects were enrolled this randomized, double-blind placebo-controlled study. Each dose level (0.03–20 mg/kg) investigated separate groups 8 (6 on inclacumab, 2 placebo). Platelet–leukocyte...
Summary Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of (microprecipitate bulk powder formulation) to determine maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, clinical activity patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), daily days (QD or...
3005 Background: USP1 is a deubiquitinase that regulates DNA damage response pathways, such as Translesion Synthesis and Fanconi Anemia pathways. KSQi potent, selective small molecule inhibitor of with anti-proliferative activity in tumors HRR mutations. The combination PARP inhibitors (PARPi) showed strong synergy Ovarian TNBC PDX models, supporting this clinical trial. Methods: This 2-part study: Part 1 dose escalation using BOIN design explored safety, pharmacokinetics (PK),...
Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden patients with polycythemia vera (PV) phase 1 study. This open-label 2 study evaluated idasanutlin hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin administered once daily on days through 5 of each 28-day cycle. The primary end point composite response (hematocrit control spleen...
To assess the safety, tolerability, pharmacokinetics, and efficacy of rituximab (RTX) in pediatric patients with granulomatosis polyangiitis (GPA) or microscopic (MPA).The Pediatric Polyangiitis Rituximab Study was a phase IIa, international, open-label, single-arm study. During initial 6-month remission-induction phase, received intravenous infusions RTX (375 mg/m2 body surface area) glucocorticoids once per week for 4 weeks. follow-up period, could receive further treatment, including RTX,...
This multicenter, randomized, double-blind, placebo-controlled, ascending-dose study investigated the pharmacokinetics, pharmacodynamic effects, safety, and tolerability of aleglitazar, a novel peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) dual agonist. After 3-week washout period, 71 patients with type 2 diabetes received either single oral dose aleglitazar (20, 50, 100, 300, 600, or 900 microg) placebo, followed by once-daily dosing for 6 weeks. Few adverse...
In Alzheimer's disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production toxic reactive oxygen species (ROS), which are thought contribute pathogenesis. Inhibition MAO-B enzyme may restore brain levels monoaminergic neurotransmitters, reduce formation ROS and neuroinflammation (reactive astrocytosis), potentially leading neuroprotection. Sembragiline (also referred as RO4602522, RG1577 EVT 302 in previous communications) is a potent,...
This study was performed to determine the effect of two protease inhibitors, saquinavir (SQV, oral 1000 mg bid) boosted by ritonavir (RTV, 100 bid), on pharmacokinetics (PK) methadone in opiate-dependent HIV-negative patients stable maintenance therapy. a two-center, open-label, one-sequence cross-over, multiple-dose 13 who were therapy (oral, 60–120 qd). All continued treatment days 2–15. received SQV/RTV combination with from PK assessed day 1 (alone) and 15 when combined at steady state....
A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was developed to investigate the epileptogenic activity of imipenem in rats. Initially, animals received an intravenous infusion at a rate 2.65 mg min(-1) for 30 min. Blood samples were collected drug assay, and electroencephalogram (EEG) recorded during postinfusion. dramatic delay observed between concentrations serum EEG effect; this effect accompanied by tremors partial seizures. Indirect-effect models failed describe these...
OBJECTIVE: This study was designed to investigate the pharmacokinetic effects of coadministration saquinavir/ritonavir with efavirenz at steady state. METHODS: Healthy volunteers in this open-label, two-arm, one-sequence, two-period crossover (planned enrollment 40 participants) were randomized one two treatment arms: those Arm 1 scheduled receive 1,000/100 mg orally twice daily for 29 days and 600 once starting on day 15 continuing through 29; participants 2 29. Assessments included vital...
Aim The Phase Ib GERSHWIN study (NCT01680991) assessed the pharmacokinetic (PK) profile of obinutuzumab following multiple intravenous (i.v.) doses to Chinese patients with B‐cell lymphomas, and compared findings previous PK studies in mainly Caucasian (non‐Chinese) patients. Methods was an open‐label, single‐arm intervention study. Patients aged >18 years CD20+ relapsed/refractory chronic lymphocytic leukaemia (CLL), diffuse large lymphoma (DLBCL) or follicular (FL) were enrolled from...
Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability G exposure and association progression-free survival (PFS) average concentration over induction (CmeanIND ) lymphoma treated plus chemotherapy (bendamustine, CHOP, or CVP) the GALLIUM trial.Individual exposures were obtained from established population...
Aims Rituximab is standard care in a number of lymphoma subtypes, including follicular (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and high proportion relapse. Obinutuzumab novel anti‐CD20 monoclonal antibody improved efficacy over rituximab. It approved for previously untreated chronic lymphocytic leukaemia (CLL), use bendamustine rituximab‐relapsed/refractory FL. Methods Using described population pharmacokinetic (PK) model...
A fixed-dose subcutaneous (s.c.) formulation of the anti-CD20 antibody, rituximab, has been developed to address safety, infusion time, and patient comfort concerns relating intravenous (i.v.) dosing, approved based upon a pharmacokinetic (PK)-clinical bridging strategy, which demonstrated noninferiority s.c. vs. i.v. dosing in malignancies, including follicular lymphoma (FL) chronic lymphocytic leukemia (CLL). clinical development plan was undertaken identify rituximab doses achieving...