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. The cox proportional hazards model with only treatment as the time-varying predictor estimated a statistically significant benefit of veliparib monotherapy compared to placebo monotherapy (hazard ratio, 0.49; 95%CI, 0.33-0.73) and a modest, non-statistically significant benefit (hazard ratio, 0.81; 95%CI, 0.62-1.05) of adding veliparib to carboplatin/paclitaxel. Inclusion of exposure as an additional time-varying predictor in the cox proportional hazards model indicated a flat exposure-response relationship between the veliparib exposure and PFS when veliparib was administered in combination with carboplatin/paclitaxel or as monotherapy. The exposure-safety analysis did not reveal any meaningful exposure-dependent trend in the incidence of adverse events of interest. These analyses support the dose regimen of veliparib (120 mg twice daily) in combination with carboplatin/paclitaxel and continuation of veliparib (300-400 mg twice daily) as monotherapy if carboplatin/paclitaxel were discontinued before disease progression in this patient population. This study is registered with ClinicalTrials.gov with a registration ID: NCT02163694.

A phase 1 study of the pan-bromodomain and extraterminal inhibitor mivebresib (ABBV-075) alone or in combination with venetoclax in patients with relapsed/refractory acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous malignancy driven by genetic and epigenetic factors. Inhibition of bromodomain and extraterminal (BET) proteins, epigenetic readers that play pivotal roles in the regulation of genes relevant to cancer pathogenesis, constitutes a novel AML treatment approach. METHODS: In this first-in-human study of the pan-BET inhibitor mivebresib as monotherapy (MIV-mono) or in combination with venetoclax (MIV-Ven), the safety profile, efficacy, and pharmacodynamics of mivebresib were determined in patients with relapsed/refractory AML (ClinicalTrials.gov identifier NCT02391480). Mivebresib was administered at 3 monotherapy dose levels (1.5, 2.0, or 2.5 mg) or in combination with venetoclax (400 or 800 mg). RESULTS: Forty-four patients started treatment: of 19 who started MIV-mono, 5 went on to receive MIV-Ven combination therapy after disease progression and a washout period. Twenty-five patients started MIV-Ven, resulting in a total of 30 patients treated with the combination. The most common mivebresib-related treatment-emergent adverse events were dysgeusia (74%), decreased appetite (42%), and diarrhea (42%) in the MIV-mono group and decreased appetite (44%), vomiting (44%), and nausea (40%) in the MIV-Ven group. Serious adverse events occurred in 14 patients (74%) who received MIV-mono and in 22 patients (88%) who received MIV-Ven. In the MIV-mono group, responses were complete remission with incomplete blood count recovery in 1 patient and resistant disease in 15 patients. In the MIV-Ven group, responses were complete remission in 2 patients, partial remission in 2 patients, morphologic leukemia-free state in 2 patients, resistant disease in 12 patients, and aplasia in 1 patient. The pharmacodynamic effects of mivebresib were proportional to dose and drug exposure. CONCLUSIONS: Mivebresib was tolerated and showed antileukemic effects as monotherapy and in combination with venetoclax in patients with relapsed/refractory AML. LAY SUMMARY: Mivebresib is a novel drug that influences the way cancer cells read genetic information. Mivebresib was tested together with venetoclax in patients with acute myeloid leukemia after standard medicines failed and the disease returned, or when standard medicine was unavailable. Adverse effects were described for different drug doses, and the dose that is tolerable was determined. In some patients, their leukemia improved for some time. More studies are necessary to determine whether mivebresib can be used to treat acute myeloid leukemia.

A Population Pharmacokinetic Meta-Analysis of Veliparib, a PARP Inhibitor, Across Phase 1/2/3 Trials in Cancer Patients.

Veliparib (ABT-888) is a poly(ADP-ribose) polymerase inhibitor in development for the treatment of high-grade ovarian cancer or BRCA-mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1-compartment model with linear clearance and first-order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (Vc /F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on Vc /F. Mild and moderate renal impairment increased veliparib median (95%CI) steady-state AUC (AUCss ) by 27.3% (23.7%-30.9%) and 65.4% (56.0%-75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%-23.9%) lower AUCss compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%-20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P-glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.

Pharmacokinetics of Posaconazole Suspension in Lung Transplant Patients with and without Cystic Fibrosis.

Invasive fungal infections (IFIs) are common among lung transplant recipients (LTRs). Posaconazole is an important antifungal agent for both prophylaxis and treatment of IFIs; however, detailed pharmacokinetic data are limited among LTRs, particularly those with cystic fibrosis (CF). Our objective was to conduct a pharmacokinetic study of posaconazole oral suspension among LTRs, with particular attention to patients with CF. We enrolled 20 LTRs, 7 with CF and 13 with other underlying lung diseases. Average daily doses in CF and non-CF patients were 829 and 862 mg, respectively. After ≥5 days of treatment, only 4 patients had average plasma concentrations of >0.7 µg/ml. Average steady-state plasma concentrations were 61% lower in CF patients (0.233 µg/ml) than in non-CF LTRs (0.594 µg/ml; P = 0.03). The average dose-normalized plasma area-under-the-curve (AUC) values were also lower in CF (0.007 h·µg/ml) than in non-CF LTRs (0.02 h·µg/ml; P = 0.02). The weight-normalized apparent oral clearance values were 2.51 and 0.74 liters/h/kg among CF and non-CF LTRs, respectively (P = 0.005). Despite significant interpatient variability, plasma trough concentrations were strongly correlated with posaconazole AUC across all LTRs (r(2) = 0.95, P < 0.0001). Taken together, our study highlights a critical need to incorporate new formulations of posaconazole into prophylaxis and treatment strategies for LTRs, particularly those with CF. Future pharmacokinetic studies of both tablet and intravenous formulations must consider LTR-specific factors and incorporate a therapeutic drug monitoring plan in this patient population.

A Pilot Study of Continuous Infusion of Mycophenolate Mofetil for Prophylaxis of Graft-versus-Host-Disease in Pediatric Patients.

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose-escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC(0-24) of 40 to 80 µg·hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 µg/mL. During the CI schedule, MPA AUC(0-24) was maintained at a mean of 40.1 µg·hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 µg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in pediatric HCT recipients compared with stable pediatric renal transplant patients or adult transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation.