Assessment of Safety and Efficacy of Estetrol in Postmenopausal Women With Advanced Estrogen Receptor Positive (ER+) Breast Cancer

A Phase I/II Clinical Trial Assessing Safety and Efficacy of Estetrol (E4) in Postmenopausal Women With Advanced Estrogen Receptor Positive (ER+) Breast Cancer

This is a multi-center, open-label, phase I/IIa trial, dose-escalation study with a 3 + 3 cohort design to determine the recommended dose of estetrol for the treatment of patients with advanced breast cancer. After completing phase I part of the study (i.e. 4 weeks of treatment), patients will receive further treatment for 8 weeks at their individual phase I dose level (phase IIa part of the study).

Inclusion Criteria:

• Postmenopausal women with ER-positive and HER2-negative locally advanced and/or metastatic breast cancer, who progressed on standard therapies or for whom standard therapies are intolerant;
• Patients should have experienced a natural or surgical menopause at least 5 years ago;
• Failure of anti-estrogen treatment with tamoxifen and aromatase inhibitor(s) due to the development of resistance or unacceptable side effects with this treatment;
• No undiagnosed vaginal bleeding;
• No treatment with fulvestrant within 6 months of start of treatment;
• Life expectancy at least 6 months;
• Tumour assessment (CT scan) before the start of the E4 treatment;
• Body mass index (BMI) between (≥) 18 and (≤) 35 kg/m2;
• Able to swallow an oral medication;
• Acceptable values of hematological parameters, liver and kidney function and calcium levels;
• Acceptable values of hemostasis parameters (as of second cohort);
• Eastern Cooperative Oncology Group (ECOG) Performance Status: 0-2 (as of second cohort);
• Reasonable physical and mental health as judged by the investigator and determined by physical examination, clinical laboratory assessments and vital signs;
• Willing to give informed consent in writing.

Exclusion Criteria:

• Uncontrolled nausea, vomiting, or diarrhea;
• History of venous or arterial thromboembolic disease or a known defect in the blood coagulation system;
• History of severe cardiac events or life threatening cardiac dysrhythmia (as of second cohort);
• Patients who have unstable angina or clinical congestive heart failure (as of second cohort);
• Uncontrolled hypertension, i.e. systolic blood pressure 160 mmHg and/or diastolic blood pressure 100 mmHg in the last 6 months with or without medication;
• Diabetes mellitus with poor glycaemic control in the last 6 months (HbA1c above 7.5%);
• Any other serious disease including systemic lupus erythematosus and untreated cholelithiasis;
• Smoking >10 cigarettes/day;
• Use of any other cancer therapy including radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, chemotherapy, or use of other investigational agents at the start of treatment.