Clinical trial NCT02718144: Assessment of Safety and Efficacy of Estetrol in Postmenopausal Women With Advanced Estrogen Receptor Positive (ER+) Breast Cancer
Official title: A Phase I/II Clinical Trial Assessing Safety and Efficacy of Estetrol (E4) in Postmenopausal Women With Advanced Estrogen Receptor Positive (ER+) Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Breast Neoplasms
Keywords: dose-escalation
safety
dose-limiting toxicity
Lead sponsor: Pantarhei Oncology B.V.
Sponsor class: OTHER
First posted: 2016-03-24
Enrollment: 12
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: 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).


Eligibility criteria: 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.

Primary outcomes:
measure: The number of patients with a dose limiting toxicity (DLT)
timeFrame: 4 weeks
Secondary outcomes:
measure: Questionnaire on estrogen deficiency symptoms
timeFrame: 12 weeks
measure: Pharmacokinetics: estetrol trough levels
timeFrame: 2 weeks, 4 weeks, 8 weeks
measure: Preliminary anti-tumour response according to RECIST 1.1
timeFrame: 12 weeks
Other outcomes:
measure: Number of patients with Adverse Events (AEs)
timeFrame: 12 weeks
Locations:
city: Mainz
country: Germany
facility: Katholisches Klinikum Mainz
city: Mainz
country: Germany
facility: Universitatsmedizin Mainz
Study officials:
References:
citation: Singer CF, Bennink HJ, Natter C, Steurer S, Rudas M, Moinfar F, Appels N, Visser M, Kubista E. Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer. Carcinogenesis. 2014 Nov;35(11):2447-51. doi: 10.1093/carcin/bgu144. Epub 2014 Jul 5.
citation: Visser M, Kloosterboer HJ, Bennink HJ. Estetrol prevents and suppresses mammary tumors induced by DMBA in a rat model. Horm Mol Biol Clin Investig. 2012 Apr 1;9(1):95-103. doi: 10.1515/hmbci-2012-0015.