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Purpose: AMEERA-5 investigated amcenestrant (oral selective estrogen receptor [ER] degrader) plus palbociclib versus letrozole plus palbociclib as first-line treatment for ER-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced/metastatic breast cancer (aBC)., Materials and Methods: In AMEERA-5 (ClinicalTrials.gov identifier: NCT04478266), a double-blind, double-dummy, international phase III trial, adult pre-/post-menopausal women and men without previous systemic therapy for ER+/HER2- aBC were randomly assigned 1:1 to amcenestrant 200 mg once daily + standard palbociclib dosage (125 mg once daily, 21 days on/7 days off) or letrozole 2.5 mg once daily + standard palbociclib dosage, stratified by de novo metastatic disease, postmenopausal women, and visceral metastasis. The primary end point was progression-free survival (PFS), compared using a stratified log-rank test with one-sided type I error rate of 2.5%. Secondary end points included overall survival (key secondary), pharmacokinetics, and safety., Results: Between October 14, 2020, and December 2, 2021, 1,068 patients were randomly assigned to amcenestrant + palbociclib (N = 534) or letrozole + palbociclib (N = 534). At the interim analysis (median follow-up 8.4 months), the stratified hazard ratio for PFS was 1.209 (95% CI, 0.939 to 1.557; one-sided P value = .9304); therefore, the study was stopped for futility. The 6-month PFS rate was 82.7% (95% CI, 79.0 to 85.8) with amcenestrant + palbociclib versus 86.9% (95% CI, 83.5 to 89.6) with letrozole + palbociclib. In the amcenestrant + palbociclib versus letrozole + palbociclib groups, treatment-emergent adverse events (any grade) occurred in 85.6% versus 85.4% of patients and grade ≥3 events in 46.3% versus 60.8%, respectively., Conclusion: The AMEERA-5 study was discontinued on the basis of the recommendation of the data monitoring committee at the interim futility analysis. No new safety signals were identified.

A joint modeling framework was developed using data from 75 patients of early amcenestrant phase I-II AMEERA-1-2 dose escalation and expansion cohorts. A semi-mechanistic tumor growth inhibition (TGI) model was developed. It accounts for the dynamics of sensitive and resistant tumor cells, an exposure-driven effect on tumor proliferation of sensitive cells, and a delay in the initiation of treatment effect to describe the time course of target lesion tumor size (TS) data. Individual treatment exposure overtime was introduced in the model using concentrations predicted by a population pharmacokinetic model of amcenestrant. This joint modeling framework integrated complex RECISTv1.1 criteria information, linked TS metrics to progression-free survival (PFS), and was externally evaluated using the randomized phase II trial AMEERA-3. We demonstrated that the instantaneous rate of change in TS (TS slope) was an important predictor of PFS and the developed joint model was able to predict well the PFS of amcenestrant phase II monotherapy trial using only early phase I-II data. This provides a good modeling and simulation tool to inform early development decisions., (© 2024 Sanofi R & D. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2- advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional 18 F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status., (© 2022. The Author(s).)

Background: For estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), the current standard first-line treatment includes an aromatase inhibitor in combination with a cyclin-dependent kinase 4/6 inhibitor. When resistance occurs, often related to the occurrence of ESR1 mutations, selective estrogen receptor modulators or degraders (SERDs) may be used, alone or in combination regimens. Amcenestrant (SAR439859), an optimized oral SERD, has shown clinical antitumor activity in combination with palbociclib in patients with ER+/HER2- ABC and, as monotherapy, in patients with and without ESR1 mutations. Here, we describe the study design of AMEERA-5, an ongoing, prospective, phase 3, randomized, double-blind, multinational study comparing the efficacy and safety of amcenestrant plus palbociclib versus letrozole plus palbociclib in patients with advanced (locoregional recurrent or metastatic) ER+/HER2- breast cancer., Methods: Patients are pre-/postmenopausal women and men with no prior systemic therapy for ABC. The planned enrollment is 1066 patients. Patients are randomized 1:1 to either amcenestrant 200 mg plus palbociclib 125 mg or letrozole 2.5 mg plus palbociclib 125 mg. Amcenestrant, letrozole, and their matching placebos are taken once daily continuously; palbociclib is taken once daily for 21 days, followed by 7 days off-treatment for a 28-day cycle. Treatment continues until disease progression, unacceptable toxicity, or decision to stop treatment. Pre-/perimenopausal women and men receive goserelin subcutaneously. Randomization is stratified by de novo metastatic disease, menopausal status, and visceral metastases. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival; others are safety, pharmacokinetics, and quality of life., Conclusions: AMEERA-5 is evaluating the efficacy and safety of amcenestrant in combination with palbociclib as first-line therapy in pre-/postmenopausal women and men with ER+/HER2- ABC., Clinicaltrials Identifier: NCT04478266., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AB reports consulting or advisory roles at Biotheranostics, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Genentech, Immunomedics, Merck, Novartis, Pfizer, Philips, Puma Biotechnology, Radius Health, Sanofi, and Spectrum Pharmaceuticals; consulting or advisory roles (to his institution) with Genentech/Roche, Immunomedics, Innocrin Pharma, Novartis, Pfizer, and Radius Health; and research funding to his institution from AstraZeneca/Daiichi Sankyo, Genentech, Immunomedics, Merck, Novartis, Pfizer, Radius Health, and Sanofi. JC reports stock/ownership interest at MedSIR; honoraria from Celgene, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Samsung; consulting or advisory role at AstraZeneca, Athenex, Bioasis, Biothera, Boehringer Ingelheim, Celgene, Cellestia Biotech, Clovis Oncology, Daiichi Sankyo, ERYTECH Pharma, GlaxoSmithKline, Kyowa Kyrin, Leuko, Lilly, Merck Sharp & Dohme, Merus, Polyphor, Roche, Seattle Genetics, and SERVIER; and research funding to his institution from ARIAD, AstraZeneca, Baxalta, Bayer, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur, Puma Biotechnology, Queen Mary University of London, and Roche; and travel/accommodations/expenses from Daiichi Sankyo, Eisai, Novartis, Pfizer, and Roche. SAH reports stock/ownership interests at Ideal Implant and ROM Tech; research funding to her institution from Ambryx, Amgen, Arvinas, Bayer, Biomarin, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Immunomedics, Lilly, Macrogenics, Merrimack, Novartis, OBI Pharma, Pfizer, Phoenix Molecular Designs, Pieris Pharmaceuticals, Puma Biotechnology, Radius Health, Sanofi, Seattle Genetics, and Zymeworks; and travel/accommodations/expenses from Lilly; and other relationships with Pfizer and Roche. SD reports consulting or advisory roles (to her institution) with AstraZeneca and Pierre Fabre; research funding to her institution from AstraZeneca, Exact Sciences, Lilly, Novartis, Pfizer, Puma Biotechnology, Roche/Genentech, and Sanofi; and travel/accommodations/expenses from AstraZeneca, Pfizer, and Roche. HI reports honoraria from AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kirin, Lilly Japan, Pfizer, and Taiho Pharmaceutical; consulting or advisory roles with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly Japan, Novartis, and Pfizer; and research funding to his institution from AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly Japan, MSD, Nihonkayaku, Novartis, Pfizer, and Sanofi. ZMS reports no disclosures. DK, PC, QL, and SCC are employees of Sanofi and may hold shares and/or stock options in the company. VP is a former employee of Sanofi and a current employee of Bayer. JO discloses honoraria from AbbVie, Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eisai, Genentech, Genomic Health, GRAIL, HERON, Immunomedics, Ipsen, Jounce Therapeutics, Lilly, Merck, Myriad Pharmaceuticals, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, Roche, Samsung, Sanofi, Seattle Genetics, and Syndax; consulting or advisory roles with AbbVie, Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Eisai, Genentech, Genomic Health, GRAIL, HERON, Immunomedics, Ipsen, Jounce Therapeutics, Lilly, Merck, Myriad Pharmaceuticals, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, Roche, Samsung, Sanofi, Seattle Genetics, and Syndax; speakers’ bureau fees from AstraZeneca, Lilly, Novartis, and Pfizer; research funding to her institution from Seattle Genetics; and travel/accommodations/expenses from AbbVie, Agendia, Amgen, AstraZeneca, Celgene, Eisai, Genomic Health, GRAIL, Ipsen, Jounce Therapeutics, Lilly, Myriad Pharmaceuticals, Novartis, Pfizer, Puma Biotechnology, Roche, Sanofi, and Seattle Genetics., (© The Author(s), 2022.)

The inducible p25 overexpression mouse model recapitulate many hallmark features of Alzheimer's disase including progressive neuronal loss, elevated Aβ, tau pathology, cognitive dysfunction, and impaired synaptic plasticity. We chose p25 mice to evaluate the physical and functional integrity of the blood-brain barrier (BBB) in a context of Tau pathology (pTau) and severe neurodegeneration, at an early (3 weeks ON) and a late (6 weeks ON) stage of the pathology. Using in situ brain perfusion and confocal imaging, we found that the brain vascular surface area and the physical integrity of the BBB were unaltered in p25 mice. However, there was a significant 14% decrease in cerebrovascular volume in 6 weeks ON mice, possibly explained by a significant 27% increase of collagen IV in the basement membrane of brain capillaries. The function of the BBB transporters GLUT1 and LAT1 was evaluated by measuring brain uptake of d-glucose and phenylalanine, respectively. In 6 weeks ON p25 mice, d-glucose brain uptake was significantly reduced by about 17% compared with WT, without any change in the levels of GLUT1 protein or mRNA in brain capillaries. The brain uptake of phenylalanine was not significantly reduced in p25 mice compared with WT. Lack of BBB integrity, impaired BBB d-glucose transport have been observed in several mouse models of AD. In contrast, reduced cerebrovascular volume and an increased basement membrane thickness may be more specifically associated with pTau in mouse models of neurodegeneration., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Efficacy of drugs aimed at treating central nervous system (CNS) disorders rely partly on their ability to cross the cerebral endothelium, also called the blood-brain barrier (BBB), which constitutes the main interface modulating exchanges of compounds between the brain and blood. In this work, we used both, conventional pharmacokinetics (PK) approach and in situ brain perfusion technique to study the blood and brain PK of PKRinh, an inhibitor of the double-stranded RNA-dependent protein kinase (PKR) activation, in mice. PKRinh showed a supra dose-proportional blood exposure that was not observed in the brain, and a brain to blood AUC ratio of unbound drug smaller than 1 at all tested doses. These data suggested the implication of an active efflux at the BBB. Using in situ brain perfusion technique, we showed that PKRinh has a very high brain uptake clearance which saturates with increasing concentrations. Fitting the data to a Michaelis-Menten equation revealed that PKRinh transport through the BBB is composed of a passive unsaturable flux and an active saturable protein-mediated efflux with a k m of ≅ 3 μM. We were able to show that the ATP-binding cassette (ABC) transporter P-gp (Abcb1), but not Bcrp (Abcg2), was involved in the brain to blood efflux of PKRinh. At the circulating PKRinh concentrations of this study, the P-gp was not saturated, in accordance with the linear brain PKRinh PK. Finally, PKRinh had high brain uptake clearance (14 μl/g/s) despite it is a good P-gp substrate (P-gp Efflux ratio ≅ 3.6), and reached similar values than the cerebral blood flow reference, diazepam, in P-gp saturation conditions. With its very unique brain transport properties, PKRinh improves our knowledge about P-gp-mediated efflux across the BBB for the development of new CNS directed drugs., (Copyright © 2018. Published by Elsevier B.V.)

Background: Phosphoinositide 3-kinase (PI3K) β is the dominant isoform for PI3K activity in many phosphatase and tensin homolog (PTEN)-deficient tumor models. This was a first-in-human study to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301, a potent PI3Kβ-selective inhibitor (clinicaltrials.gov identifier NCT01673737)., Methods: Successive cohorts of patients with advanced solid tumors received increasing doses of oral SAR260301 according to a Bayesian escalation with an overdose-control process based on the occurrence of dose-limiting toxicity in the first 28-day cycle. Adverse events, tumor response, PK, and the effect of food on PK were evaluated. Target engagement was assessed in platelets. Physiologically-based PK modeling was used for exposure predictions., Results: Twenty-one patients received treatment at doses ranging from 100 mg once daily to 440 mg/m 2 twice daily. Dose-limiting toxicities included 1 episode of grade 3 pneumonitis (400 mg twice daily) and 1 grade 3 γ-glutamyltransferase increase (600 mg twice daily). The maximum tolerated dose was not reached. The most frequently occurring treatment-related adverse events were nausea, vomiting, and diarrhea (14% each). Pharmacologically active concentrations were reached, but SAR260301 was rapidly cleared, and exposures associated with antitumor activity in preclinical models were not maintained at the highest dose tested. Food further decreased SAR260301 exposure., Conclusions: SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. Cancer 2018;124:315-24. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Aim: Applying physiologically-based pharmacokinetic (PBPK) modelling in paediatric cancer drug development is still challenging. We aimed to demonstrate how PBPK modelling can be applied to optimize dose and sampling times for a paediatric pharmacokinetic (PK) bridging study in oncology and to compare with the allometric scaling population PK (AS-popPK) approach, using docetaxel as an example., Methods: A PBPK model for docetaxel was first developed for adult cancer patients using Simcyp® and subsequently used to predict its PK profiles in children by accounting for age-dependent physiological differences. Dose (mg m(-2) ) requirements for children aged 0-18 years were calculated to achieve targeted exposure in adults. Simulated data were then analyzed using population PK modelling with MONOLIX® in order to perform design optimization with the population Fisher information matrix (PFIM). In parallel, the AS-popPK approach was performed for the comparison., Results: The PBPK model developed for docetaxel adequately predicted its PK profiles in both adult and paediatric cancer patients (predicted clearance and volume of distribution within 1.5 fold of observed data). The revised dose of docetaxel for a child over 1.5 years old was higher than the adult dose. Considering clinical constraints, the optimal design contained two groups of 15 patients, having three or four sampling times and had good predicted relative standard errors (RSE<30%) for almost all parameters. The AS-popPK approach performed reasonably well but could not predict for very young children., Conclusion: This research shows the clinical utility of PBPK modelling in combination with population PK modelling and optimal design to support paediatric oncology development., (© 2015 The British Pharmacological Society.)

Background: To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2)., Patients and Methods: In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks., Results: Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg., Conclusion: Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks., (Copyright © 2012 Elsevier Ltd. All rights reserved.)