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Background Endocrine therapy in combination with a targeted cyclin-dependent kinase (CDK) 4/6 inhibitor is the clinical standard for treatment of ER+/HER2- advanced breast cancer. Amcenestrant (SAR439859) is an optimized oral SERD with potent dual activity that antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway. In previous arms of the AMEERA-1 study, amcenestrant, as monotherapy or in combination with the CDK4/6 inhibitor palbociclib, demonstrated antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- advanced breast cancer. The objective of Arm 5 of the AMEERA-1 study is to evaluate safety and antitumor activity of amcenestrant in combination with the CDK4/6 inhibitor abemaciclib for patients with ER+/HER2- advanced breast cancer. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Arm 5 investigates dose escalation (Part J) and dose expansion (Part K), of amcenestrant in combination with abemaciclib. Postmenopausal women with ER+/HER2- advanced breast cancer, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. In Arm 5 (Parts J and K), ≤ 1 prior line of a single endocrine therapy for advanced disease is allowed. Prior treatment with fulvestrant or any other SERD is not allowed; in addition, prior therapy with CDK4/6 inhibitors for advanced disease is not allowed. Part J allows ≤ 1 prior chemotherapy for advanced disease, while prior chemotherapy for advanced disease is not allowed in Part K. Additional exclusion criteria in Arm 5 are prior drugs targeting the phosphoinositide 3-kinase axis; history of or concurrent pneumonitis; and history of or concurrent venous thromboembolism (i.e., deep vein thrombosis, pulmonary embolism, or cerebral venous sinus thrombosis). Part J evaluates the selected amcenestrant dose for combination therapy plus abemaciclib 150 mg twice daily (BID) (the approved standard dose) or abemaciclib 100 mg BID, taken in 28-day cycles. Additional dose levels of amcenestrant may be explored based on safety and pharmacokinetics (PK). The objective of Part J is to determine the recommended dose (RD) of abemaciclib in combination with the selected amcenestrant dose for combination therapy, based on preliminary safety, PK, and antitumor activity data. The primary endpoint in Part J is the incidence of treatment-related dose-limiting toxicities (DLTs) at Cycle 1. Approximately up to 12 DLT-evaluable patients will be needed to establish the RD of abemaciclib in combination with amcenestrant in Part J. In Part K, approximately 20 patients will be treated at the RD of abemaciclib for combination therapy with amcenestrant, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. Funding: Sanofi. Citation Format: Mario Campone, Sarat Chandarlapaty, Aditya Bardia, Patrick Neven, Katarina Petrakova, Peter Kabos, Valentina Boni, Sofia Braga, Marina Celanovic, Patrick Cohen, Alice Gosselin, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Hannah Linden. Ameera-1 Arm 5: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with abemaciclib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-04.

Background Amcenestrant is an optimized oral SERD with potent dual activity of ER antagonism and degradation resulting in inhibition of ER signaling. Amcenestrant monotherapy or combination with palbociclib showed antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- mBC. PIK3CA mutations are associated with endocrine resistance in ER+/HER2- patients (pts). Published data support the addition of the PI3Kα inhibitor alpelisib to SERD therapy for these pts. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Parts F and G investigate safety run-in and dose expansion, respectively, of amcenestrant in combination with alpelisib. Postmenopausal women with ER+/HER2- advanced breast cancer, PIK3CA mutated in tumor tissue or cfDNA, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. Pts must have progressed on an aromatase inhibitor plus CDK4/6 inhibitor as first-line therapy for advanced disease. Part F allows ≤ 1 prior chemotherapy for advanced disease; no prior chemotherapy is allowed in Part G. Exclusion criteria in Parts F and G include prior drugs targeting the PI3K axis, type 1 diabetes, uncontrolled type 2 diabetes, history of severe cutaneous reactions, and ongoing osteonecrosis of the jaw. Part F assesses dose-limiting toxicities and pharmacokinetics (PK) of a standard dose of amcenestrant plus the approved dose of alpelisib (300 mg once daily). Additional amcenestrant doses or a lower dose of alpelisib may be explored based on safety and PK. The primary objective in Part F is to confirm the recommended phase 2 dose (RP2D) of amcenestrant in combination with alpelisib, based on safety. In Part G, approximately 34 pts will be treated at the RP2D, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. This study is currently recruiting participants. This abstract was previously submitted to the 2021 European Society for Medical Oncology Annual Congress. Funding: Sanofi. Citation Format: Mario Campone, Aditya Bardia, Peter Kabos, Sarat Chandarlapaty, Patrick Neven, Valentina Boni, Simon Lord, Sylvaine Cartot-Cotton, Marina Celanovic, Alice Gosselin, Vasiliki Pelekanou, Hannah M Linden. AMEERA-1 : Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with alpelisib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-)PIK3CA-mutated advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-03.

Background Amcenestrant (SAR439859) is an optimized oral SERD with potent dual activity that antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway. Amcenestrant, as monotherapy or in combination with palbociclib, has shown antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- advanced breast cancer. Published data support the addition of targeted therapy to endocrine therapy for patients with ER+/HER2- advanced breast cancer. The objective of Arm 4 of the AMEERA-1 study is to evaluate safety and antitumor activity of amcenestrant in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus for patients with ER+/HER2- advanced breast cancer. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Arm 4 investigates dose escalation (Part H) and dose expansion (Part I), of amcenestrant in combination with everolimus. Postmenopausal women with ER+/HER2- advanced breast cancer, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. In Arm 4 (Parts H and I), ≤ 1 prior line of a single endocrine therapy for advanced disease is allowed. Patients must have progressed on a non-steroidal aromatase inhibitor plus cyclin-dependent kinase 4/6 inhibitor as first-line therapy for advanced disease. Prior treatment with fulvestrant or any other SERD is not allowed. Part H allows ≤ 1 prior chemotherapy for advanced disease; no prior chemotherapy for advanced disease is allowed in Part I. Exclusion criteria in Arm 4 include prior drugs targeting the phosphoinositide 3-kinase axis; history of or concurrent pneumonitis; history of severe cutaneous reactions; type 1 diabetes; uncontrolled type 2 diabetes; uncontrolled hypercholesterolemia, hypertriglyceridemia, and hyperglycemia; any uncontrolled infection; uncontrolled stomatitis, angioedema due to angiotensin-converting enzyme inhibitors, and impaired wounds. Part H evaluates the selected amcenestrant dose for combination therapy plus everolimus 10 mg once daily (QD) (the approved standard dose) or everolimus 5 mg QD, taken in 28-day cycles. Additional amcenestrant doses may be explored based on safety and pharmacokinetics (PK). The objective of Part H is to determine the recommended dose (RD) of everolimus in combination with the selected amcenestrant dose for combination therapy, based on preliminary safety, PK, and antitumor activity data. The primary endpoint in Part H is the incidence of treatment-related dose-limiting toxicities (DLTs) at Cycle 1. Approximately up to 12 DLT-evaluable patients will be needed to establish the RD of everolimus in combination with amcenestrant in Part H. In Part I, approximately 12 patients will be treated at the RD of everolimus for combination therapy with amcenestrant, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. Funding: Sanofi. Citation Format: Mario Campone, Patrick Neven, Katarina Petrakova, Sofia Braga, Marina Celanovic, Patrick Cohen, Alice Gosselin, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Valentina Boni. Ameera-1 Arm 4: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with everolimus in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-02.

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 6/2021 = 415 pts. Bardia A, et al., J Clin Oncol. 2019; 37 (15 suppl):1054. Funding: Sanofi. This abstract was accepted and previously presented at the 2021 American Society of Clinical Oncology Annual Meeting. All rights reserved. Citation Format: Aditya Bardia, Javier Cortes, Sara Hurvitz, Suzette Delaloge, Hiroji Iwata, Zhi-Ming Shao, Dheepak Kanagavel, Patrick Cohen, Qianying Liu, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Joyce O’Shaughnessy. AMEERA-5 : A randomized, double-blind phase 3 study of amcenestrant (SAR439859) + palbociclib versus letrozole + palbociclib for previously untreated ER+/HER2- advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-08.

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/m2 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.

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.

1058 Background: AMEERA-1 (NCT03284957) investigates amcenestrant, an oral SERD, as monotherapy and combined with targeted therapies in ER+/HER2– mBC. Here we report data from dose escalation (Part C) and dose expansion (Part D) of amcenestrant + palbo. Methods: Patients (pts) were postmenopausal women with ER+/HER2– mBC and ≥ 6 mos prior advanced endocrine therapy (ET) or adjuvant (adj) ET resistance (relapse on adj ET started ≥ 24 mos ago or < 12 mos after completing adj ET). Prior chemotherapy (≤ 1) for advanced disease was allowed; targeted therapies were not except ≤ 1 CDK4/6i in Part C. Part C assessed dose-limiting toxicities (DLTs) and aimed to establish the recommended phase 2 dose (RP2D) for amcenestrant (200 or 400 mg once daily [QD], in 28-day cycles) in combination with palbo (125 mg QD for 21 days on/ 7 days off). Safety (treatment-emergent adverse events [TEAEs] and lab abnormalities per CTCAE v4.03) and pharmacokinetics (PK) were evaluated. Antitumor activity at the RP2D for amcenestrant + palbo was evaluated in a subset of Part C pts and Part D, according to RECIST v1.1, determined locally by investigators. Results: Feb 8, 2021 data cutoff. In Part C (n = 15; 200 mg: 9; 400 mg: 6), no DLTs occurred and amcenestrant 200 mg QD was selected as the RP2D with palbo, based on PK and safety data. In the pooled safety population at the RP2D (n = 39; Part C: 9; Part D: 30), median (range) age was 59 y (33–86) with ECOG PS 0 (74.4%) or 1 (25.6%) and 2 (1–6) organs involved. Immediate prior therapy was neo/adj (41.0%, all ET resistant) or advanced (59.0%, range 1–4 lines). Median (range) exposure was 32 wks (1–66) with 59.0% pts on ongoing therapy. No amcenestrant dose reductions occurred; 25.6% had ≥ 1 palbo dose reduction. Most common non-hematological TEAEs related to amcenestrant were Grade 1–2 nausea and fatigue (17.9% each), asthenia and hot flush (10.3% each); to palbo were fatigue (30.8%), nausea (25.6%), asthenia and dysgeusia (10.3% each). Two pts discontinued due to AEs. The majority (94.9%) had neutrophil count decrease (53.8% Grade ≥ 3). Preliminary antitumor activity after at least 6 cycles of therapy (unless early treatment discontinuation) is reported in the table below. Conclusions: In pts with ER+/HER2– mBC, safety at the RP2D of amcenestrant + palbo was favorable, with no safety signals of bradycardia or eye disorders. Preliminary antitumor activity was observed (ORR: 31.4% and CBR: 74.3%). Clinical trial information: NCT03284957 .[Table: see text]

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.

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 km 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.

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).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.Twenty-one patients received treatment at doses ranging from 100 mg once daily to 440 mg/mSAR260301 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.

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.

2564 Background: SAR260301 (SAR) is a potent (IC50 52 nM) PI3Kb inhibitor selectively inhibiting the PI3K pathway in PTEN-null models. This phase I Sanofi sponsored study was initiated to evaluate ...

SAR650984 is a novel humanized monoclonal antibody specifically targeting the CD38. , A phase 1 dose escalation study is being conducted in patients with confirmed CD38+ hematological malignancies to determine safety of SAR650984, to establish the MTD and the biologically active dose, and to characterize the PK and PD after repeated IV administration. Methods: The study design was composed of 2 parts. The first one was an accelerated phase with 1 to 3 patients per dose cohort from 0.0001 mg/kg to 0.1 mg/kg and the second phase includes 3 to 7 patients per dose cohort between 0.3 and 20 mg/kg every 2 weeks. An additional 6 patient cohort was added at 10 mg/kg every week. Results: 34 out of the 39 treated patients were Relapsed Refractory Multiple Myeloma (MM) patients. SAR650984 was well tolerated. Overall Response Rate (CR + PR) for dosing cohorts of ≥1mg/kg is 32% (2 MR, 5 PR, 2 CR of 28). Pharmacodynamics were evaluated by measuring CD38 density and its occupancy by the drug in bone marrow on cancer cells, using a validated quantitative flow cytometry method. This parameter has been correlated with the dose and exposure levels. Receptor Occupancy (RO) could be detected starting from the 1 mg/kg dose. From 5 mg/kg dose level, preliminary results demonstrated receptor occupancy greater than 70% (maximum observed: 97.7%). From 0.0001 to 0.01 mg/kg doses, no or limited PK parameters could be calculated. The PK profile was not linear with a decrease in clearance when the dose was increased suggesting target mediated clearance. Based on individual modeling, a moderate to high variability (CV% = 49 to 130%) was observed on estimated systemic total clearance, regardless of the dose group. At the10 mg/kg Q2W, the shape of the PK profile suggests saturation of the target. All MM patients (N=6) at cycle 1 had SAR650984 plasma trough levels consistently above the 10 µg/ml level which is associated with anti-tumor activity in mouse xenograft studies (Cssmin of the lowest pharmacological active dose). At 20 mg/kg Q2W, in 2/3 MM patients, SAR650984 plasma trough levels from cycle 2 were above the concentration needed to eradicate the tumor (129 µg/mL) in the same animal model, based on the Simeoni et al modelling approach. These preliminary phase 1 safety and efficacy results are associated with a favorable PK/PD profile and justify the progression of the program to phase 2. NCT : NCT01084252 Citation Format: Marie-Laure L. Ozoux, Hélène Guillemin, Marie-Hélène H. Pascual, Sylvaine Cartot-Cotton, Christine Veyrat-Follet, Delphine Valente, Maxime Moulard, Christine Mauriac, Antoine Deslandes, Dorothee Semiond. A first-in-human phase I study of SAR650984, a humanized anti-CD38 antibody in patients with CD38+ hematological malignancies: Preliminary PK and PD results of escalation phase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2908. doi:10.1158/1538-7445.AM2014-2908

The PI3K/mTOR pathway is involved in promoting tumor cell proliferation, survival and metastasis. The development of new anticancer therapies targeting different components of this pathway has been motivated by the identification of somatic PIK3CA missense mutations as well as the high frequency of loss of negative regulatory proteins such as the tumor suppressor PTEN. In this last case, the abnormal activation of downstream effectors is mediated by PI3Kβ. PTEN deficiency has also been reported to be involved in the resistance to a variety of anticancer therapies. The preceding findings support investigation into selective modulators of the lipid kinase activity of p110β as agents for the treatment of PTEN-deficient tumors, with potentially reduced on-target adverse events described for pan-PI3K inhibitors currently undergoing clinical trials. SAR260301 is a selective PI3Kβ lipid kinase inhibitor that has demonstrated higher potency in vitro on p110β (IC50= 52 nM) than on p110δ and p110α isoforms and no or weak activity against p110γ, mTOR and a wide range of protein kinases (>400 enzymes). The potency and selectivity against the intended target was further confirmed in mechanistic cellular models (IC50 = 32 nM, p110β; 26- and 88-fold selective over p110δ and p110α, respectively). Moreover, SAR260301 also modulates pAkt levels exclusively in PTEN-deficient tumor cell lines with IC50 values ranging from 39 to 310 nM and from 20 to 209 nM for pAkt-S473 and pAkt-T308, respectively. When administered orally, the compound shows dose and time-dependent inhibition of the PI3K pathway in human PTEN-deficient tumor xenografts in mice. In these models, target engagement correlates with compound exposure and is associated with good tolerability. The MAPK pathway also plays an important role in cancer and is often constitutively and simultaneously activated with the PI3K pathway. Furthermore, PTEN loss has been shown to correlate with resistance to MAPK inhibitors. Preclinical data evidencing the ability of SAR260301 to modulate pAkt levels in genetic contexts where PTEN deficiency co-exists with MAPK pathway activation, as well as the effects of combining SAR260301 with MAPK inhibitors will also be presented. The foregoing studies support ongoing Phase I clinical investigation of SAR260301 in patients with PTEN-deficient malignancies. Citation Format: Angela Virone-Oddos, Hélène Bonnevaux, Olivier Lemaitre, Loic Vincent, Franck Halley, Brigitte Demers, Véronique Charrier, Olivier Courtin, Stéphane Guérif, Laurent Besret, Pierre-Yves Abecassis, Sylvaine Cartot-Cotton, Gary Emmons, Alan Roberts, David Compton, Bin Wu, Laurent Schio, Christoph Lengauer, Carlos Garcia-Echeverria. Discovery and characterization of SAR260301, a novel PI3Kβ-selective inhibitor in clinical development for the treatment of PTEN-deficient tumors . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3258. doi:10.1158/1538-7445.AM2013-3258