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

Study Overview
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Brief Summary
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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).

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

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Estetrol


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: estetrol<br>3 + 3 design with inter-patient dose escalation | Drug: Estetrol<br>* Estetrol formulated in tablets, in escalating doses, will be investigated in patients with estrogen receptor positive (ER+) locally advanced or metastatic breast cancer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients with a dose limiting toxicity (DLT) |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Questionnaire on estrogen deficiency symptoms | Quality of Life will be assessed by means of a questionnaire on estrogen deficiency symptoms. | 12 weeks | 
| Pharmacokinetics: estetrol trough levels |  | 2 weeks, 4 weeks, 8 weeks | 
| Preliminary anti-tumour response according to RECIST 1.1 |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dose-escalation, safety, dose-limiting toxicity