Search

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.

TPS1104 Background: Selective estrogen receptor degraders (SERDs) block estrogen receptor (ER) associated signaling and have created interest for treating patients (pts) with advanced ER+ breast cancer (BC). Fulvestrant is currently the only SERD available for advanced BC but requires intramuscular administration, limiting the applied dose, exposure and receptor engagement. Amcenestrant (SAR439859) is an oral SERD that binds with high affinity to both wild-type and mutant ER, blocking estradiol binding and promoting up to 98% ER degradation in preclinical studies. In the phase I AMEERA-1 study of pretreated pts with ER+/HER2- advanced BC, amcenestrant 150–600 mg once daily (QD) showed a mean ER occupancy of 94% with plasma concentrations > 100 ng/mL and a favorable safety profile (Bardia, 2019; data on file). Combination therapy with amcenestrant + palbociclib (palbo) was also evaluated as part of this ongoing phase I study. CDK 4/6 inhibitors (CDK4/6i) combined with an aromatase inhibitor (AI), the gold standard for first line treatment for advanced breast cancer, prolong progression free survival (PFS) in pts with no prior treatment for ER+/HER2- advanced BC, but OS benefit has not been shown yet in postmenopausal pts. There remains a clinical need for more effective treatments in this setting. Methods: AMEERA-5 (NCT04478266) is an ongoing, prospective, randomized, double-blind phase III study comparing the efficacy and safety of amcenestrant + palbo with that of letrozole + palbo in pts with advanced, locoregional recurrent or metastatic ER+/HER2- BC who have not received prior systemic therapy for advanced disease. The study includes men, pre/peri-menopausal (with goserelin) and post-menopausal women. Pts with progression during or within 12 months of (neo)adjuvant endocrine therapy using any of the following agents are excluded: AI, selective estrogen receptor modulators, CDK4/6i. Pts are randomized 1:1 to either continuous amcenestrant 200 mg or letrozole 2.5 mg QD orally with matching placebos; both combined with palbo 125 mg QD orally (d1–21 every 28-d cycle). Randomization is stratified according to disease type (de novo metastatic vs recurrent disease), the presence of visceral metastasis, and menopausal status. The primary endpoint is investigator assessed progression free survival (PFS) (RECIST v1.1). Secondary endpoints are overall survival, PFS2, objective response rate, duration of response, clinical benefit rate, pharmacokinetics of amcenestrant and palbo, health-related quality of life, time to chemotherapy, and safety. Biomarkers will be measured in paired tumor biopsies and cell free deoxyribonucleic acid (cfDNA) over time. Target enrolment = 1066 pts; enrolment as of 1/2021 = 33 pts. Bardia A, et al., J Clin Oncol. 2019; 37 (15 suppl):1054 Clinical trial information: NCT04478266 .

Background Endocrine therapy targeting estrogen receptor (ER) signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER- breast cancer. AMEERA-4 (NCT04191382; ACT16106) is a 14-day preoperative, non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods This international, open-label, Phase 2 randomized study evaluates SAR439859 at two dose levels vs the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing AMEERA-1 Phase 1/2 study (NCT03284957; TED14856) in metastatic breast cancer. Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0-1, and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological complete response will also be assessed. The study is currently recruiting. Funding: Sanofi. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved. Citation Format: Mario Campone, Christina Herold, Qiuyan Wang, Vasiliki Pelekanou, Sylvaine Cartot-Cotton, Bethany Ling. AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-11.

Background Endocrine therapy (ET) targeting ER signaling is the mainstay of care for ER+ metastatic BC. There remains an unmet need in patients whose tumors become resistant to currently available ET. Selective ER degraders (SERDs) were developed to overcome resistance to existing ER-directed therapies by both competitively antagonizing and degrading ERs, while exploiting continued dependence of the tumor on ER signaling. SAR439859 is a potent SERD with robust preclinical ER degrading activity. In AMEERA-1, a Phase 1 dose escalation trial, SAR439859, had a favorable safety profile with no dose-limiting toxicities across all doses (20-600 mg once per day; QD). ER occupancy generally exceeded > 87% with plasma concentrations > 100 ng/mL. Overall response rate was 6.3% and the recommended Phase 2 monotherapy dose was 400 mg QD. Methods AMEERA-3 is an international, prospective, open-label, randomized Phase 2 study (NCT04059484; ACT16105) designed to assess safety and efficacy of SAR439859 in pts with ER+ (>1%)/HER2− metastatic or locally advanced BC progressing on ≥ 6 months of continuous ET (0-2 lines in the metastatic setting). Prior cyclin-dependent kinase (CDK) inhibitors are allowed. Exclusion criteria include: Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, life expectancy < 3 months, > 1 chemotherapy or targeted therapy in the metastatic setting, concomitant illness and factors potentially affecting SAR439859 absorption. Patients are randomized 1:1 to SAR439859 400 mg QD orally or physician’s choice of endocrine monotherapy (fulvestrant, tamoxifen, aromatase inhibitor). Patients receive 28-day cycles until unacceptable toxicity, progression, death, investigator decision, or patient request. Stratification factors include visceral metastases, prior CDK4/6 inhibitors, and ECOG PS. The primary endpoint is progression-free survival (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints include overall survival, response rate, duration of response, clinical benefit, pharmacokinetics, quality of life and safety. Target enrollment: n = 282; current enrollment: n = 9. Funding: Sanofi. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved. Citation Format: Sara Tolaney, Irfan Cicin, Rafael Betancourt, Arlene Chan, Diego Kaen, Peter Kaufman, Suzette Delaloge, Qianying Liu, Sylvaine Cartot-Cotton, Amele Amrate, Vasiliki Pelekanou, Katharine Cuff. AMEERA-3, a phase 2 trial of SAR439859 vs endocrine monotherapy in pre- and post-menopausal, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (her2−), locally advanced or metastatic breast cancer (BC) with prior exposure to hormonal therapies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-09.

TPS1108 Background: Endocrine therapy targeting ER signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER2- breast cancer. This study is a 14-day preoperative non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods: This international, open-label, Phase II randomized study (NCT04191382; ACT16106) evaluates SAR439859 at two dose levels versus the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing Phase I/II study (NCT03284957; TED14856) in metastatic breast cancer (Campone. SABCS 2019. P5-11-02). Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0–1 and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological Complete Response will also be assessed. The study is currently recruiting; target enrollment: n = 126. Clinical trial information: NCT04191382 .

TPS1107 Background: Endocrine therapy (ET) targeting ER signaling is the mainstay of care for ER+ metastatic BC. There remains an unmet need in patients (pts) whose tumors become resistant to currently available ET. Selective ER degraders (SERDs) were developed to overcome resistance to existing ER-directed therapies by both competitively antagonizing and degrading ERs, while exploiting continued dependence of the tumor on ER signaling. SAR439859 is a potent SERD with robust preclinical ER degrading activity. In a Phase I dose escalation trial, SAR439859 demonstrated a favorable safety profile with no dose-limiting toxicities across all doses (20–600 mg QD). ER occupancy generally exceeded > 87% with plasma concentrations > 100 ng/mL. Overall response rate was 6.3% and clinical benefit rate was 50% (Campone. SABCS 2019. P5-11-02). The recommended Phase II monotherapy dose was 400 mg QD. Methods: This international, prospective, open-label, randomized Phase II study (NCT04059484; ACT16105) assesses safety and efficacy of SAR439859 in pts with ER+ (> 1%)/HER2- metastatic or locally advanced BC progressing on ≥ 6 months of continuous ET (0–2 lines in the metastatic setting). Prior CDK inhibitors are allowed. Exclusion criteria include Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, life expectancy < 3 months, > 1 chemotherapy or targeted therapy in the metastatic setting, concomitant illness and factors potentially affecting SAR439859 absorption. Pts are randomized 1:1 to SAR439859 400 mg QD orally or physician’s choice of endocrine monotherapy (fulvestrant, tamoxifen, aromatase inhibitor). Pts receive 28-day cycles until unacceptable toxicity, progression, death, investigator decision or pt request. Stratification factors include visceral metastases, prior CDK4/6 inhibitors, and ECOG PS. Primary endpoint is progression-free survival (RECIST v1.1). Secondary endpoints include overall survival, response rate, duration of response, clinical benefit, pharmacokinetics, quality of life and safety. Target enrollment: n = 282; current enrollment: n = 9. Funding: Sanofi Clinical trial information: NCT04059484 .

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.

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 5 mg/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.