The Study of Oral Steroid Sulphatase Inhibitor BN83495 Versus Megestrol Acetate (MA) in Women With Advanced or Recurrent Endometrial Cancer

Study Overview
=================
Brief Summary
-----------------
This trial will explore the safety and efficacy of BN83485 compared to Megestrol Acetate (MA) on progression free survival (PFS) in post menopausal patients with endometrial cancer.

Detailed Description
-----------------
The Primary Objective in this study is to determine the antitumour efficacy of BN83495 measured by the percentage of women with advanced or recurrent endometrial cancer who have neither progressed nor died after 6 months of treatment.

Official Title
-----------------
A Phase II International Multicentre Randomised Open Label Study of Oral Steroid Sulphatase Inhibitor BN83495 Versus Megestrol Acetate (MA) in Women With Advanced or Recurrent Endometrial Cancer

Conditions
-----------------
Endometrial Cancer

Intervention / Treatment
-----------------
* Drug: BN83495
* Drug: Megestrol Acetate (MA)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of written informed consent prior to any study related procedures Post-menopausal or ovariectomised female patients over the age of 18 years with advanced or recurrent endometrial carcinoma Histologically confirmed diagnosis endometrial carcinoma (primary tumour or metastasis) Not eligible for surgery or radiotherapy alone, at Investigator's discretion Documented Estrogen Receptor (ER) positivity in the primary tumour or in the metastatic tissue if the primary tumour is unavailable (ER positivity is defined by at least 10% positive cells) No other history of malignant disease except treated basal cell or in situ cervical carcinoma in the previous 5 years. In case of previous malignant disease, pathological confirmation of metastatic endometrial cancer will be done at Investigator's discretion Eastern Cooperative Oncology Group (ECOG) Performance status ≤2 At least one measurable disease site minimum indicator lesion size: 20 mm (conventional techniques) or 10 mm (spiral CT scan) target lesions not situated in irradiated area Life expectancy ≥6 months Adequate organ function as defined by the following criteria: Haemoglobin ≥10 g/dL Absolute neutrophil count (ANC) ≥1500/μL Platelets ≥100,000/μL Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥50 ml/min Serum AST and serum ALT ≤2.5x ULN or AST and ALT ≤5x ULN if liver metastases Total serum bilirubin ≤1.5x ULN Serum albumin ≥3.0 g/dL Cardiac function ≤New York Heart Association (NYHA) class II Patients must have recovered from surgery, radiotherapy and toxicities of adjuvant chemotherapy treatment if applicable Patients must be willing and able to participate in a clinical trial (including the completion of all necessary study procedures) Patients must be able to swallow oral medication Exclusion Criteria: Use of any investigational agent in the 4 weeks prior to enrollment in this study Prior systemic treatment for endometrial cancer (including hormonal treatment, chemotherapy, antiangiogenic or targeted therapies)with the exception of chemotherapy in the adjuvant setting, having been completed at least 6 months prior to randomisation Known central nervous system (CNS) metastases Ongoing cardiac dysrhythmias of National Cancer Institute Common Toxicity Criteria Adverse Events (NCI CTC AE) grade ≥2, atrial fibrillation of any grade, QTcF interval >460 msec. Patients with contraindications to Megestrol Acetate (MA) including hypersensitivity to one of the drug product, any active arterial or venous thromboembolic event and/or uncontrolled hypertension. Patients receiving anticoagulation for a prior thromboembolic event may be enrolled in the study at the Investigator's discretion Concomitant use of carbonic anhydrase II inhibitors (e.g. acetazolamide, dichlorphenamide, methazolamide) History of hypersensitivity to BN83495 or drugs with a similar chemical structure Likely to require treatment during the study with drugs that are not permitted by the study protocol Abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardise the patient's safety or decrease the chance of obtaining satisfactory data needed to achieve the objective(s) of the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A- BN 83495- 40mg<br>After eligibility is confirmed, subjects will be randomised at baseline. The randomisation number and associated treatment for the total study will be allocated by an Interactive Voice Response System (IVRS) service | Drug: BN83495<br>* BN83495 will be administered as a 40 mg tablet once a day orally<br>|
| Active Comparator: B- MA - 160mg<br>After eligibility is confirmed, subjects will be randomised at baseline. The randomisation number and associated treatment for the total study will be allocated by an Interactive Voice Response System (IVRS) service | Drug: Megestrol Acetate (MA)<br>* MA will be administered orally as 160mg daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Women With Advanced or Recurrent Endometrial Cancer Who Have Neither Progressed Nor Died | Subject continuation in the study and Response Evaluation Criteria in Solid Tumours (RECIST) assessment has been based on investigator assessment and not on central review. The 6 month timepoint is defined as the treatment start date +183 days (26 weeks). | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Event (AE) | Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life threatening/disabling and Grade 5: Death | Up to Day 28 follow-up | 
| Tolerability of BN83495 Based on Length of Exposure | Length of exposure includes interruptions. | Up to 2 years | 
| Tolerability of BN83495 Based on Cumulative Dose Administered | Cumulative dose is the actual total dose administered. | Up to 2 years | 
| Tolerability of BN83495 Based on Dose Interruptions and Reason for Interruptions | Percentage of participants who had dose interruptions and reason for interruptions as AE, study treatment forgotten, and other reasons. | Up to 2 years | 
| Percentage of Participants >65 Years of Age With No Change or Deterioration, Improvement of <10%, or Improvement of ≥10% on the EuroQoL Score | EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) is a participant answered questionnaire scoring 5 dimensions: Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome. | Up to week 32 | 
| Percentage of Participants With Clinical Benefit [Including Completed Response (CR), Partial Response (PR), and Stable Disease (SD)] ≥12 Weeks | CR: Disappearance of all known disease & no new sites / disease related symptoms confirmed at least 12 weeks after initial documentation. Disappearance of all non-target lesions. Normalization of tumor marker level confirmed at least 12 weeks after initial documentation. PR: Minimum 30% decrease in sum of the longest diameters of target lesions, taking as a reference the baseline sum of the longest diameters confirmed at least 12 weeks after initial documentation. PR is also recorded when all measurable disease has completely disappeared, but a non-measurable component (i.e., ascites) is still present but not progressing. As well as persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above normal limits. RECIST defines SD for target lesions as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, no occurrence of progression disease for non-target lesions, and no new lesions. | Up to 2 years | 
| Percentage of Participants With Overall Response (OR) Including CR and PR |  | Up to 2 years | 
| Percentage of Participants With First Documentation of Objective Tumour Progression From Randomisation |  | Up to 2 years | 
| Duration of Response (DR) in Responders | DR is defined as period from the time that measurement criteria are first met for CR or PR until first date of documented Progressive Disease (PD) or death. DR was assessed in participants with a best overall response of CR or PR. | At 2 years | 
| Overall Survival (OS) | OS is defined as the time from the date of enrollment to the date of death due to any cause. | At 2 years | 
| Progression Free Survival (PFS): Time From Randomisation Until Objective Tumour Progression or Death From Any Cause |  | Up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Endometrial cancer, Antitumour efficacy in women with advanced endometrial cancer