A5087989455- Renal cell carcinoma treatment
- PARP inhibition in cancer therapy
- Renal and related cancers
- Glioma Diagnosis and Treatment
- Multiple Myeloma Research and Treatments
- Advanced Breast Cancer Therapies
- Prostate Cancer Treatment and Research
- Drug Transport and Resistance Mechanisms
- Economic and Financial Impacts of Cancer
- CAR-T cell therapy research
- Monoclonal and Polyclonal Antibodies Research
- Cancer therapeutics and mechanisms
- HER2/EGFR in Cancer Research
- Neuroendocrine Tumor Research Advances
- Lung Cancer Research Studies
- Lanthanide and Transition Metal Complexes
- Nanoparticle-Based Drug Delivery
- Chronic Lymphocytic Leukemia Research
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- Brain Metastases and Treatment
- Cancer Treatment and Pharmacology
- Biosimilars and Bioanalytical Methods
- Pancreatic and Hepatic Oncology Research
- Pharmacogenetics and Drug Metabolism
Pfizer (United States)
2018-2025
St. Jude Children's Research Hospital
2009-2023
University of Tennessee Health Science Center
2009-2023
Bristol-Myers Squibb (Switzerland)
2023
University of Florida
2020
Columbus Oncology and Hematology Associates
2020
Novartis (China)
2020
Novartis (United States)
2017-2018
Novartis (Switzerland)
2018
University at Buffalo, State University of New York
2013-2014
BackgroundThe phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Here, we report updated efficacy safety data, together exploratory biomarker analyses, from the study.Patients methodsA total of 668 postmenopausal women HR+,...
Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled without prior BCMA-directed therapy (n = 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by...
PARP inhibitors in combination with androgen receptor-targeted therapy have demonstrated potential the treatment of metastatic castration-resistant prostate cancer (mCRPC). Here, we describe design and rationale multinational, phase III, two-part TALAPRO-2 study comparing talazoparib plus enzalutamide versus placebo as a first-line for patients mCRPC or without DNA damage response (DDR) alterations. This has two co-primary end points: radiographic progression-free survival (rPFS) by blinded...
8008 Background: Studies in the MagnetisMM program (MM-1, NCT03269136; MM-3, NCT04649359; MM-9, NCT05014412) enrolled pts treated with prior BCMA-directed therapies. A pooled analysis from these studies evaluated efficacy and safety of elranatamab RRMM exposure to therapy. Methods: Eligible received at least 1 PI, IMiD, anti-CD38 antibody, therapy (ADC and/or CAR-T cells). Pooled included MM-1 (n = 13) who SC 215−1000 µg/kg; MM-3 64) MM-9 9) RP2D, 76 mg QW. Efficacy endpoints were assessed...
Cytokine release syndrome (CRS) is a common, acute adverse event associated with T‐cell redirecting therapies such as bispecific antibodies (BsAbs). The nature of CRS events data makes it challenging to capture an unbiased exposure–response relationship commonly used models. For example, simple logistic regression models cannot handle traditional time‐varying exposure, and static exposure metrics chosen at early time points lower priming doses may underestimate the incidence CRS. Therefore,...
Abstract Purpose: To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation erlotinib its metabolite, OSI-420. Experimental Design: After oral administration to wild-type ATP-binding cassette (ABC) transporter-knockout mice (Mdr1a/b−/−, Abcg2−/−, Mdr1a/b−/−Abcg2−/−, Abcc4−/−), plasma was collected brain extracellular fluid (ECF) sampled using intracerebral microdialysis. A pharmacokinetic model fit OSI-420 concentration–time data, (PBrain)...
Abstract Background In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression-free survival (PFS) compared physician's choice of chemotherapy (PCT) in germline BRCA1/2-mutated HER2-negative advanced breast cancer (ABC). Herein, safety profile is explored detail. Materials and Methods Overall, 412 patients received ≥1 dose (n = 286) or PCT 126). Adverse events (AEs) were evaluated, including timing, duration, potential overlap selected...
Ribociclib (KISQALI), a cyclin‐dependent kinase 4/6 inhibitor approved for the first‐line treatment of HR+/HER2– advanced breast cancer with an aromatase inhibitor, is administered no restrictions on concomitant gastric pH‐elevating agents or food intake. The influence proton pump inhibitors (PPIs) ribociclib bioavailability was assessed using 1) biorelevant media solubility, 2) physiologically based pharmacokinetic (PBPK) modeling, 3) noncompartmental analysis (NCA) clinical trial data, and...
Despite evidence for a role prolactin signaling in breast and prostate tumorigenesis, receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum levels may be biomarker receptor inhibition.Results from the pharmacokinetic pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals insufficient exposure to LFA102 have resulted lack of antitumor efficacy.Based on preclinical data, combination therapy with those novel agents targeting hormonal...
Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of topotecan, a substrate the ATP-binding cassette (ABC) transporters P-glycoprotein (Pgp/MDR-1) and breast cancer resistance protein (BCRP/ABCG2). The effect modulating these on topotecan penetration in gliomas has not been thoroughly studied. Thus, we performed intracerebral microdialysis mice bearing orthotopic human (U87 MT330) assessed tumor ECF...
Abstract Purpose: PROTECT, a phase III, randomized, placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant renal cell carcinoma setting. The relationship between exposure (Ctrough) was evaluated. Patients Methods: Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early Ctrough) 250 16 20 (late Ctrough). Pazopanib pharmacokinetic (PK) data analyzed via population model approach. Relationship Ctrough dose intensity...
Ribociclib is approved in combination with endocrine therapy as initial endocrine‐based for HR‐positive and HER2‐negative advanced breast cancer. primarily metabolized by CYP3A4 and, vitro , an inhibitor of CYP3A CYP1A2. Ritonavir (a strong inhibitor) increased ribociclib 400 mg single‐dose area under the plasma concentration‐time curve (AUC) 3.2‐fold, whereas rifampin inducer) decreased AUC 89% healthy volunteers (HVs). Multiple doses midazolam (CYP3A substrate) 3.8‐fold caffeine (CYP1A2...
Topotecan is a substrate of the ATP-binding cassette transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). To define role these in topotecan penetration into ventricular cerebrospinal fluid (vCSF) brain parenchymal extracellular (ECF) compartments, we performed intracerebral microdialysis on transporter-deficient mice after an intravenous dose (4 mg/kg). vCSF unbound lactone was measured as ratio vCSF-to-plasma area under concentration-time curves. The mean +/-...
Abstract Guidance from the U.S. Food and Drug Administration (FDA) European Medicines Agency recommends using Child‐Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations oncology compounds patients HI are commonly based on classification. In clinical practice, National Cancer Institute (NCIc), is used evaluating function decisions patients. This work evaluated discordance between 2 systems impact...
B‐cell maturation antigen (BCMA)‐targeting immunotherapies (e.g., chimeric receptor T cells (CAR‐T) and bispecific antibodies (BsAbs)) have achieved remarkable clinical responses in patients with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune related to T‐cell activation cytokine elevations leading release syndrome (CRS) some patients, which can be potentially life‐threatening. However, systematic evaluation of the risk CRS BCMA‐targeting...
Objectives: Bispecific antibodies (BsAb) are a rapidly evolving treatment modality for multiple myeloma (MM). Elranatamab, an approved BsAb, forms immune synapse between T-cells via surface marker CD3 and B-cell maturation antigens (BCMA) on tumor cells1. Membrane-bound BCMA can undergo shedding from the cell surface, leading to circulation of soluble (sBCMA), which is associated with disease burden reduces drug exposure may impact efficacy. Establishing recommended dose based non-clinical...
Objectives: Cytokine release syndrome (CRS) is a systemic inflammatory response that occurs after the administration of T cell engaging therapies such as bispecific antibodies (BsAbs) and results in elevated circulating cytokine levels some rare cases secondary organ dysfunction1. To decrease risk severity, current management strategies involve step-up dosing premedication. A quantitative systems pharmacology (QSP) model CRS could streamline development innovative medicines by assessing...
Elranatamab is a BCMA-CD3 bispecific antibody approved for the treatment of relapsed or refractory multiple myeloma. Cytokine release syndrome one most common adverse events associated with antibodies. We aimed to determine optimal elranatamab dosing regimen mitigating cytokine syndrome. Safety, pharmacokinetics, and exposure–response were analyzed across four clinical studies (MagnetisMM-1, MagnetisMM-2, MagnetisMM-3, MagnetisMM-9). Different priming regimens evaluated these included...
In vitro data show that talazoparib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein transporters. This open-label, 2-arm, drug-drug interaction Phase 1 study in patients with advanced solid tumours assessed the effect of P-gp inhibitor (itraconazole) inducer (rifampicin) on pharmacokinetics single dose talazoparib. The safety tolerability without itraconazole or rifampicin were also assessed.Thirty-six enrolled (Arm A [itraconazole], n = 19; Arm B [rifampicin],...