Abstract OT1-04-05: Phase 1/2 dose-escalation and expansion study investigating SAR439859, a potent, oral, selective estrogen receptor degrader, +/- palbociclib in metastatic breast cancer
Authors: Campone Mario , Bardia Aditya , Ulaner Gary A , Chandarlapaty Sarat , Gosselin Alice , Doroumian Séverine , Celanovic Marina , Linden Hannah M 
Published: March 2020

Abstract
Background: Anti-estrogen therapy remains the gold standard for prevention and treatment of estrogen receptor-positive (ER+)/human epidermal growth factor receptor-negative (HER2-) breast cancer. However, resistance to anti-estrogen therapy is often observed in the clinic and frequently occurs through reactivation of ER transcriptional function. Unlike other classes of anti-estrogen therapy that have one mode of action, selective ER degraders (SERDs) block ER function through both competitive antagonism of the ligand binding pocket and induced degradation of the receptor. These have the potential to overcome multiple resistance mechanisms including ligand-independent mutations in ER 1. SAR439859 is a potent, oral SERD with improved preclinical efficacy and pharmaceutical properties compared with other SERDs. This study investigates SAR439859 +/- the cyclin-dependent kinase 4/6 inhibitor, palbociclib, in postmenopausal women with ER+/HER2- metastatic breast cancer.
Methods: This prospective, open-label, non-randomized Phase 1/2 study (NCT03284957; TED14856) assesses SAR439859 single agent at dose levels increasing from 20 mg/day up to the maximum administered dose (Part A) followed by cohort expansion at the recommended dose (RD; Part B). The study will also assess two dose levels of SAR439859, in combination with palbociclib 125 mg/day (Days 1-21 in 28-day cycles; Part C) followed by cohort expansion (Part D). The protocol has been amended to investigate the safety, pharmacokinetics and pharmacodynamics of alternative SAR439859 doses in an exploratory patient population. These patients will receive SAR439859 as two daily doses of up to 300 mg taken 12 hours apart with a maximum dose intensity of 600 mg/day (Table). Postmenopausal women with ER+/HER2- metastatic breast cancer, who have received ≥ 6 months of prior endocrine therapy, are eligible. Patients are permitted to have received ≤ 3 (Part A) or ≤ 1 (Parts B-D) prior chemotherapies (including antibody drug conjugates) for metastatic disease. Patients in Parts C and D with early progression on adjuvant therapy or progression on adjuvant endocrine therapy &lt; 12 months after ending therapy are eligible. Exclusion criteria include Eastern Cooperative Oncology Group performance status ≥ 2, concomitant illness (including those related to HIV or hepatitis and other cancers ≤ 3 years) and factors potentially affecting absorption of SAR439859 or palbociclib. Study endpoints include assessment of dose-limiting toxicities, determination of maximum tolerated dose and RD in dose escalation (Parts A and C), and objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in dose expansion (Parts B and D). 18F-fluoroestradiol positron emission tomography scan between Days 11-15 in Part A will assess ER availability. Safety, pharmacokinetics and response will be evaluated for Parts A-D. As of May 9, 2019, 69 patients have been enrolled (Part A: n = 16; B: n = 47; C: n = 6; D: n = 0). Funding: Sanofi.
Table. DLs for determining the RD for SAR439859 alone (Part A) and in combination with palbociclib (Part C)Part ADLaDose (mg)ScheduleDL(-1)10QDDL120QDDL1bis50QDDL2100QDDL2bis150QDDL3200QDDL4400QDDL4bis200BIDDL5600QDDL5bis300BIDPart Cb,cDL1One DL below Part A QD RDQDDL2Part A QD RDQDDL3dPart A BID RDBIDaAdditional intermediate or higher DLs can be tested after agreement between Sponsor and Investigators (study committee). A twice-daily schedule of administration may be added during the study, the starting dose will be a DL of the same dose intensity as the highest cleared DL with the daily schedule. Other schedules of administration may be added during the study.bLower dose, intermediate DLs and a BID dose regimen can be tested after agreement between Sponsor and Investigators (study committee).cAll patients will also receive palbociclib at 125 mg QD with food for 21 days of each 28-day cycle. Lower doses (e.g. 100 mg or 75 mg) can be proposed depending on tolerance.dA BID dose could be tested assuming that BID monotherapy in Part A indicates a benefit compared with the RD given QD.BID, twice daily; DL, dose level; QD, once daily; RD, recommended dose.
Citation Format: Mario Campone, Aditya Bardia, Gary A Ulaner, Sarat Chandarlapaty, Alice Gosselin, Séverine Doroumian, Marina Celanovic, Hannah M Linden. Phase 1/2 dose-escalation and expansion study investigating SAR439859, a potent, oral, selective estrogen receptor degrader, +/- palbociclib in metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-05.