Evaluation of Cardiac Repolarization in the Randomized Phase 2 Study of Intermediate- or High-Risk Smoldering Multiple Myeloma Patients Treated with Daratumumab Monotherapy.

Introduction: Daratumumab is a CD38-targeting monoclonal antibody that has demonstrated clinical benefit for multiple myeloma. Daratumumab inhibition of CD38, which is expressed on immune cell populations and cardiomyocytes, could potentially affect cardiac function. This QTc substudy of the phase 2 CENTAURUS study investigated the potential effect of intravenous daratumumab monotherapy on QTc prolongation and other electrocardiogram (ECG) parameters, including concentration-QTc effect modeling.

Subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma: Part 2 of the open-label, multicenter, dose-escalation phase 1b study (PAVO).

Intravenous daratumumab is approved for the treatment of multiple myeloma. In Part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and similar efficacy to intravenous daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of daratumumab and rHuPH20 (DARA SC).

Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial.

Background: Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab.

Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses.

Introduction: Daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for multiple myeloma. In clinical studies, the median durations of the first, second, and subsequent intravenous infusions of daratumumab were 7.0, 4.

Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS).

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules.

Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma.

Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM.

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma.

Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible.

Pharmacokinetics and Exposure-Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma.

Introduction: Daratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes.

Methods: Four clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis.

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma.

Daratumumab, a human CD38 imunoglobulin G 1κ monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy and safety, were assessed.

Influence of Disease and Patient Characteristics on Daratumumab Exposure and Clinical Outcomes in Relapsed or Refractory Multiple Myeloma.

Objective: The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM).

Patients And Methods: Baseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies-GEN501 (N = 104) and SIRIUS (N = 124).

Results: Daratumumab clearance was approximately 110% higher in IgG myeloma patients than non-IgG myeloma patients, leading to significantly lower exposure in IgG myeloma patients based on maximum trough serum concentrations (p < 0.

Pharmacokinetics of Daratumumab Following Intravenous Infusion in Relapsed or Refractory Multiple Myeloma After Prior Proteasome Inhibitor and Immunomodulatory Drug Treatment.

Daratumumab is a CD38 monoclonal antibody recently approved for the treatment of multiple myeloma (MM). We report daratumumab pharmacokinetic data from GEN501, a phase I/II dose-escalation (0.005-24 mg/kg) and dose-expansion (8 or 16 mg/kg) study, and SIRIUS, a phase II study (8 or 16 mg/kg), in relapsed or refractory MM.

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma.

Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week).

Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference.

Background: Monoclonal antibodies are promising anti-myeloma treatments. As immunoglobulins, monoclonal antibodies have the potential to be identified by serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE). Therapeutic antibody interference with standard clinical SPE and IFE can confound the use of these tests for response assessment in clinical trials and disease monitoring.

A phase I study of oral ixabepilone in patients with advanced solid tumors.

Background: Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors.

Patients And Methods: Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1-5 of a 21-day cycle.

Phase I trial of ixabepilone administered as three oral doses each separated by 6 hours every 3 weeks in patients with advanced solid tumors.

Background: Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or βIII-tubulin.

Materials And Methods: This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/dose; 150 mg on Day 1).

Lack of effect of brivanib on the pharmacokinetics of midazolam, a CYP3A4 substrate, administered intravenously and orally in healthy participants.

Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways that is under therapeutic investigation for various malignancies. Brivanib alaninate inhibits CYP3A4 in vitro, and thus there is potential for drug-drug interaction with CYP3A4 substrates, such as midazolam. The present study evaluated pharmacokinetic parameters and safety/tolerability upon coadministration of brivanib alaninate and midazolam.

Metabolism and disposition of [14C]BMS-690514, an ErbB/vascular endothelial growth factor receptor inhibitor, after oral administration to humans.

(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non-small-cell lung cancer and metastatic breast cancer. The disposition of [(14)C]BMS-690514 was investigated in nine healthy male subjects (group 1, n = 6; group 2, n = 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose.

Relative bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension.

Background And Objective: Maintenance of effective drug concentrations is essential for adequate treatment of epilepsy. Some antiepileptic drugs can be successfully administered rectally when the oral route of administration is temporarily unavailable. Oxcarbazepine is a newer antiepileptic drug that is rapidly converted to a monohydroxy derivative, the active compound.