Angelica Quartino

Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation.

Aim The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients. Methods Data were collected from 232 paediatric patients (1971 concentrations) in five studies, with a wide range of age (0.5 – 21 years), body weight (BWT; 5.9 – 125 kg), and regimens (5 – 15 mg kg–1 biweekly or triweekly). Data from 152 patients (1427 concentrations) and 80 patients (544 concentrations) were used for model building and external validation, respectively. Steady‐state exposure was simulated under BWT‐based, body surface area (BSA)‐based, ideal body weight (IBW)‐based, and tier‐based doses. NONMEM and R were used for analyses. Results Typical estimates of clearance, central volume of distribution (V1), and median half‐life were 9.04 ml h–1, 2851 ml, and 19.6 days, respectively. Clearance decreased with increasing albumin. Clearance and V1 increased with BWT and were higher in male patients. Clearance and V1 were lower in children with primary central nervous system (CNS) tumours than in children with sarcomas, resulting in 49% higher trough (Cmin) and 29% higher peak (Cmax) concentrations. BWT‐adjusted clearance and V1 remained unchanged across ages. Paediatric Cmin was similar to adult Cmin under all dosing strategies. Paediatric Cmax exceeded adult Cmax under tier‐based doses. Conclusions BWT‐adjusted pharmacokinetic parameter estimates in paediatric patients were similar to those in adults, and similar across ages. Bevacizumab exposure was higher in children with primary CNS tumours than in children with sarcomas. BSA‐based, IBW‐based, and tier‐based doses offered no substantial advantage over the BWT‐based dose currently used in adults for bevacizumab. Given the similarity in pharmacokinetics among many monoclonal antibodies, this may help to develop practical paediatric dosing guidelines for other therapeutic antibodies.

CLINICAL TRIAL DESIGN OF CREAD: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP PHASE 3 STUDY TO EVALUATE CRENEZUMAB TREATMENT IN PATIENTS WITH PRODROMAL-TO-MILD ALZHEIMER’S DISEASE

with sustained suppression at all doses. After multiple doses, change from baseline in mean CSF Ab42 was 63.2 and 79.3% in the 15 and 50 mg AZD3293 groups, respectively, with similar reductions in Ab40 (Table 2). Baseline CSFAb42 levels were similar in the healthy Japanese and non-Japanese subjects. Conclusions: AZD3293 was generally well tolerated and potently reduced plasma and CSFAb peptides in Japanese adult subjects. Reductions in CSF Ab peptides were similar to those previously reported in non-Japanese subjects with AD.

ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease

Objective To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD). Methods In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimers Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73. Results The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF β-amyloid1-42 levels that correlated with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. Conclusions Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD. Clinicaltrials.gov identifier NCT 01343966. Classification of evidence This study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because <80% of enrolled patients completed the study.Objective To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD). Methods In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimers Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73. Results The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF &bgr;-amyloid1-42 levels that correlated with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. Conclusions Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD. Clinicaltrials.gov identifier NCT 01343966. Classification of evidence This study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because <80% of enrolled patients completed the study.

A Pharmacometric Analysis of Patient-Reported Outcomes in Breast Cancer Patients Through Item Response Theory

PurposeAn item response theory (IRT) pharmacometric framework is presented to characterize Functional Assessment of Cancer Therapy-Breast (FACT-B) data in locally-advanced or metastatic breast cancer patients treated with ado-trastuzumab emtansine (T-DM1) or capecitabine-plus-lapatinib.MethodsIn the IRT model, four latent well-being variables, based on FACT-B general subscales, were used to describe the physical, social/family, emotional and functional well-being. Each breast cancer subscale item was reassigned to one of the other subscales. Longitudinal changes in FACT-B responses and covariate effects were investigated.ResultsThe IRT model could describe both item-level and subscale-level FACT-B data. Non-Asian patients showed better baseline social/family and functional well-being than Asian patients. Moreover, patients with Eastern Cooperative Oncology Group performance status of 0 had better baseline physical and functional well-being. Well-being was described as initially increasing or decreasing before reaching a steady-state, which varied substantially between patients and subscales. T-DM1 exposure was not related to any of the latent variables. Physical well-being worsening was identified in capecitabine-plus-lapatinib-treated patients, whereas T-DM1-treated patients typically stayed stable.ConclusionThe developed framework provides a thorough description of FACT-B longitudinal data. It acknowledges the multi-dimensional nature of the questionnaire and allows covariate and exposure effects to be evaluated on responses.

Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens

AIMS We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physicians Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physicians choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer. METHODS We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 maximum concentration (Cmax ), cycle 1 minimum concentration (Cmin ) and area under the concentration-time curve at steady state (AUCss ). Kaplan-Meier analyses [overall survival (OS), progression-free survival (PFS)] and logistic regression [overall response rate (ORR), safety] were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 Cmin were compared with matched TPC-treated patients. RESULTS T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 Cmin and AUCss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 Cmax . No relationship between exposure and safety was identified. HRs for the comparison of T-DM1-treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 [95% confidence interval (CI) 0.63, 1.47] for OS and 0.92 (95% CI 0.64, 1.32) for PFS. CONCLUSIONS Exposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC-treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure.

The risk of febrile neutropenia in breast cancer patients following adjuvant chemotherapy is predicted by the time course of interleukin‐6 and C‐reactive protein by modelling

Early identification of patients with febrile neutropenia (FN) is desirable for initiation of preventive treatment, such as with antibiotics. In this study, the time courses of two inflammation biomarkers, interleukin (IL)‐6 and C‐reactive protein (CRP), following adjuvant chemotherapy of breast cancer, were characterized. The potential to predict development of FN by IL‐6 and CRP, and other model‐derived and clinical variables, was explored.

BASELINE CHARACTERICS FROM A PHASE 3 TRIAL OF CRENEZUMAB IN PRODROMAL TO MILD ALZHEIMER’S DISEASE (CREAD)

Background:Alzheimer’s disease (AD) prevention trials target an earlier stage of the disease based on the idea that earlier intervention before neuron loss and symptom onset will provide improved outcomes. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) launched the first AD prevention trial in 2012 in a rare population of dominantly inherited AD mutation carriers who are destined to get the disease with near 100% penetrance. Recruitment was completed in 2015 into two parallel drug arms in the DIAN-TU adaptive prevention trial (DIAN-TU APT) platform. A major goal of public-private prevention trials is to make data available to the research community and this presentation will provide comprehensive results of baseline data. Methods: The metrics of establishing the DIAN-TU platform, start-up of sites, launch of the trial, screening, enrollment and close of enrollment measures were analyzed. Baseline demographic, clinical, cognitive, genetic, imaging including MRI, amyloid PIB PET, amyloid AV45 PET, tau AV1451 PET and biomarker results were analyzed according to protocol. Measures were compared to prior findings in the DIAN observational study. A process for DIANTU data requests was developed, approved, and activated in 2017. Results:The DIAN-TU APT platform was established in the first year with protocol, site, operational, and multiple partner start-up in this global trial. As sites were activated, enrollment rate increasedwith rapid enrollment by the end of the study. 194 participants enrolled to successfully meet enrollment goals within projected timelines. Screen fail rate (19%), recruitment source (47% DIAN-obs, 38% DIAN Expanded Registry), and completion rates of all baseline assessments (99-100%)were excellent. This trial provides comprehensive clinical, cognitive, imaging and biomarker data and samples that are being used in the final analyses and are available to address important scientific and medical questions. Conclusions:Clinical prevention trials in AD with multiple AD biomarkers are feasible and can be highly successful, even in a rare population. The results from comprehensive evaluations during trials can provide unique insights into the effects of interventions and promise to accelerate highly effective treatments and preventions for AD.

MATHEMATICAL MODEL OF AMYLOID BETA (Aβ) DYNAMICS TO ASSESS TARGET ENGAGEMENT OF SOLUBLE Aβ OLIGOMERS BY CRENEZUMAB IN THE ALZHEIMER’S DISEASE BRAIN

Therefore, the objectives of the investigation were: (1) To elucidate the relationship between the AbOs and monomeric Ab; (2) To confirm that AbOs dissociate to restore the equilibrium between Ab monomers and AbOs, following secretase inhibition. Methods: In a 4-way crossover study in cisterna-magnaported rhesus monkeys the effects of b-secretase (BACE1) (MBi5; 30, 125 mg/kg) and g-secretase (GS) (L675; 240 mg/kg) inhibitors on CSF concentrations of six biomarkers (sAPPb, Ab40, Ab42, Ab38, AbO, sAPPa) were determined. Data following treatment of the GS inhibitor was not included in the current analysis. AbO concentrations were quantified using a two-site ELISA (Savage et al. (2014)). A systems pharmacology model is proposed to characterize in a quantitative manner the biomarker responses following BACE1 inhibition on the basis of the underlying biological processes (Figure 1). Results: The APP systems model was able to integrate information from an AbO assay with the PK and APP metabolites concentration measurements in response to BACE1 inhibition. This yielded important information about the relationship between monomeric Ab species and AbOs: (i) Oligomerization was a higher order process. This means that a relatively higher change from baseline