Exposure-Response Model With Time-Varying Predictors to Estimate the Effects of Veliparib in Combination With Carboplatin/Paclitaxel and as Monotherapy: Veliparib Phase 3 Study in BRCA-Mutated Advanced Breast Cancer (BROCADE3) Trial.

BRCA-Mutated Advanced Breast Cancer (BROCADE3) is a phase 3 study, evaluating veliparib in combination with carboplatin/paclitaxel with continuation as monotherapy if carboplatin/paclitaxel is discontinued in patients with germline BRCA1/2 mutation-associated, advanced human epidermal growth factor receptor 2-negative breast cancer. The objective of the current analysis was to characterize the veliparib exposure-response relationships for efficacy (progression-free survival [PFS]) and safety in this study. Exposure-efficacy analyses of PFS were conducted using Kaplan-Meier plots and cox proportional hazards (CPH) models using treatment alone or both treatment and exposure as time-dependent predictors to estimate the effect of veliparib in combination with carboplatin/paclitaxel and as monotherapy.

Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline / mutations and hormone receptor status from the phase-3 BROCADE3 trial.

Purpose: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline (g)-associated breast cancer defined by hormone receptor (HR) and g/ mutation status.

Patients And Methods: In this phase-3, double-blind, placebo-controlled trial, patients ( = 509) with advanced HER2-negative breast cancer and g mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy.

Efficacy and safety of first-line veliparib and carboplatin-paclitaxel in patients with HER2- advanced germline BRCA+ breast cancer: Subgroup analysis of a randomised clinical trial.

Background: Addition of veliparib to carboplatin-paclitaxel, with continuation of veliparib monotherapy if carboplatin-paclitaxel was discontinued, improved progression-free survival (PFS) in patients with germline BRCA-associated locally advanced/metastatic HER2- breast cancer and ≤2 lines of previous cytotoxic therapy for metastatic disease in BROCADE3. A pre-planned subgroup analysis evaluated efficacy and safety in patients without previous cytotoxic therapy for metastatic disease.

Methods: Patients were randomised 2:1 to receive veliparib (120 mg orally BID) or placebo on days -2 to 5.

Relevance of Platinum-free Interval and Reversion Mutations for Veliparib Monotherapy after Progression on Carboplatin/Paclitaxel for g Advanced Breast Cancer (BROCADE3 Crossover).

Purpose: Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (g)-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel.

Patients And Methods: Eligible patients ( = 513) were randomized 2:1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel; patients had variable platinum-free intervals (PFI) at progression. In the placebo arm, patients were eligible to receive crossover veliparib monotherapy (300-400 mg twice daily continuous).

Progression-free survival by investigator versus blinded independent central review in newly diagnosed patients with high-grade serous ovarian cancer: Analysis of the VELIA/GOG-3005 trial.

Objective: In the phase 3 VELIA/GOG-3005 trial, veliparib added to carboplatin-paclitaxel and continued as maintenance improved progression-free survival (PFS) compared to carboplatin-paclitaxel alone in patients with newly diagnosed ovarian carcinoma. Primary analysis of PFS was by investigator (INV) assessment, with a supplemental analysis of PFS by blinded independent central review (BICR).

Methods: Patients received veliparib or placebo with carboplatin-paclitaxel (6 cycles) and as maintenance (30 additional cycles).

Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial.

Background: BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation.

Methods: BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries.

A first-in-human, phase 1, dose-escalation study of ABBV-176, an antibody-drug conjugate targeting the prolactin receptor, in patients with advanced solid tumors.

ABBV-176 is an antibody-drug conjugate composed of the humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic cross-linking pyrrolobenzodiazepine dimer (PBD; SGD-1882) targeting the prolactin receptor (PRLR), which is overexpressed in several solid tumor types. This phase 1, dose-escalation study (NCT03145909) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-176 in patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 once every 3 weeks.

Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer.

Background: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma.

Methods: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout).

Exposure-response analysis to inform the optimal dose of veliparib in combination with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer patients.

Purpose: Veliparib, a poly(ADP-ribose)-polymerase (PARP) 1 and 2 enzyme inhibitor, was administered at 120 mg twice daily (BID) for 7 days in a 21-day cycle with carboplatin/paclitaxel in the Phase 2 BROCADE study in patients with BRCA-deficient recurrent or metastatic breast cancer, a dose based on Phase 1 results. Population pharmacokinetic (PK) and exposure-response analyses were undertaken to retrospectively evaluate whether an optimal dose was used in BROCADE.

Methods: A population PK analysis was performed using data from 168 patients in BROCADE along with data from 288 subjects in another 5 studies.

A phase 1 study of PARP-inhibitor ABT-767 in advanced solid tumors with BRCA1/2 mutations and high-grade serous ovarian, fallopian tube, or primary peritoneal cancer.

Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID).

Generation of myometrium-specific Bmal1 knockout mice for parturition analysis.

Human and rodent studies indicate a role for circadian rhythmicity and associated clock gene expression in supporting normal parturition. The importance of clock gene expression in tissues besides the suprachiasmatic nucleus is emerging. Here, a Bmal1 conditional knockout mouse line and a novel Cre transgenic mouse line were used to examine the role of myometrial Bmal1 in parturition.

Preventing preterm birth: the past limitations and new potential of animal models.

The high rate of preterm birth in the USA and many other countries is a potential target for improving children's immediate health and reducing the medical problems they face as adults. The acute complications for infants born prematurely often require intensive care management and are followed by long-lasting cognitive, sensory, motor, and cardiovascular deficits that substantially limit adult capabilities and survival. The inability to effectively reduce preterm birth stems from the failure to understand normal mechanisms of parturition in humans.

Clock gene expression in gravid uterus and extra-embryonic tissues during late gestation in the mouse.

Evidence in humans and rodents suggests the importance of circadian rhythmicity in parturition. A molecular clock underlies the generation of circadian rhythmicity. While this molecular clock has been identified in numerous tissues, the expression and regulation of clock genes in tissues relevant to parturition is largely undefined.

TAK1 targeting by glucocorticoids determines JNK and IkappaB regulation in Toll-like receptor-stimulated macrophages.

Glucocorticoids potently attenuate the production of inflammatory mediators by macrophages, a primary effector of innate immunity. Activation of different macrophage Toll-like receptors (TLRs) by their respective ligands presents a powerful system by which to evaluate stimulus-dependent glucocorticoid effects in the same cell type. Here, we test the hypothesis that glucocorticoids, acting through the glucocorticoid receptor, modulate macrophage activation preferentially depending upon the TLR-selective ligand and TLR adapters.

Impaired steroidogenesis and implantation failure in Bmal1-/- mice.

Evidence in humans and rodents suggests that normal circadian rhythmicity is important for supporting reproductive function. A molecular clock underlies circadian rhythmicity. Impaired fertility is observed in some genetically altered mice with deficiencies in genes of the molecular clock, suggesting a critical role for these genes in reproduction.

Insights into parturition biology from genetically altered mice.

With the growing frequency of preterm birth, increased effort has been made to elucidate the physiology of normal and aberrant parturition. As with many developmental processes, the study of genetically altered mice has led to an increased understanding of mechanisms controlling the maintenance and resolution of pregnancy. Studies in genetically altered mice have implicated critical roles for both prostaglandin synthesis and degradation in luteolysis and the progression of labor.

Hypoxia regulates the expression of fatty acid-binding proteins in primary term human trophoblasts.

Objective: Fatty acids (FAs) are essential for fetal development. Cellular FA uptake is modulated by fatty acid-binding proteins (FABPs). We hypothesized that hypoxia regulates the expression of FABPs in human trophoblasts.

The PI3K/Akt pathway is present and functional in the preimplantation mouse embryo.

The PI3K/Akt signal transduction pathway is a well-known mediator of growth promoting and cell survival signals. While the expression and function of this pathway have been documented during early and late stages of the reproductive process, currently, there is no evidence demonstrating either the presence or function of the PI3K/Akt pathway in murine preimplantation embryos. We found, using confocal immunofluorescent microscopy and Western blot analysis, that the p 85 and p110 subunits of PI3K and Akt are expressed from the 1-cell through the blastocyst stage of murine preimplantation embryo development.