Abstract P4-13-12: Estetrol for treatment of advanced ER+ breast cancer
Authors: Schmidt M , Hönig A , Verhoeven C , Almstedt K , Battista M , Lenhard HG , Krijgh J , Coelingh Bennink H 
Published: May 2019

Abstract
Introduction: Currently, a multi-center, open-label, phase I/IIA, dose-escalation study with the fetal estrogen estetrol (E4) is ongoing in Germany in postmenopausal patients with advanced breast cancer (ABCE4 study). The objective of the study is to assess safety and tolerability of different doses of E4 (range 20-60 mg per day). In addition initial anti-tumor response will be determined.
Study design: Patients are treated for 12 weeks with E4; 4 weeks in Phase I and thereafter 8 weeks in Phase IIA. Phase I of the study will follow the traditional 3 + 3 design to determine the optimal dose in patients with advanced breast cancer. Patients are treated in cohorts of three all receiving the same dose. Occurrence of dose limiting toxicity (DLT) at completion of phase I (4 weeks treatment) will determine escalation to the next higher dose in the study. After completion of Phase I, patients will continue treatment for 8 weeks to assess preliminary anti-tumor response in Phase IIA. Treatment may continue beyond 12 weeks based on evaluation of the patient and her treating physician.
Results: Phase I of the first treatment cohort with 20 mg E4 per day has been completed. A total of six postmenopausal women with advanced breast cancer has been included in the first cohort. One patient withdrew consent before treatment with E4 started. She was replaced. Two patients discontinued the study before completion of Phase I for reasons other than DLTs. These patients were unevaluable for toxicity and were also replaced. Three patients completed Phase I. One patient discontinued the study during Phase IIA due to disease progression after 9,5 weeks of E4 treatment. One patient completed both the Phase I and IIA part of the study. She had stable disease at study completion and wanted to continue E4 treatment because of improved well-being. Tumor assessment after 24 weeks of E4 treatment showed again stable disease. One patient is presently in Phase IIA of the study.
None of the patients experienced a DLT. The 20 mg E4 dose was well tolerated by all patients. In total 17 adverse events were reported. Adverse events were mainly of mild or moderate intensity. Five of 17 events fulfilled criteria of seriousness; none of these events were considered to be related to the E4 treatment. Four events were considered to be possibly related to the E4 treatment. These events were increased endometrial thickness, dry skin, pruritus and fatigue, all of mild intensity. A remarkable finding was that three of the five patients treated with E4 reported to the investigator to “feel better” than before the start of E4 treatment. This '”feeling better” was described by one of the patients as: '”feeling less down and exhausted; instead feeling much more optimistic, powerful and positive when taking E4”.
So far anti-tumor response could be estimated in one patient. This patient, who started the study with progressive disease, had stable disease as shown by tumor assessments after 12 weeks and 24 weeks of E4 treatment.
Conclusion: Based on these results, we conclude that a daily dose of 20 mg E4 is well tolerated. The majority of patients experienced favorable subjective effects on wellbeing. The data obtained with the 20 mg dose E4 allow dose escalation to the next higher dose of 40 mg E4 per day.
Citation Format: Schmidt M, Hönig A, Verhoeven C, Almstedt K, Battista M, Lenhard HG, Krijgh J, Coelingh Bennink H. Estetrol for treatment of advanced ER+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-12.