E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced or recurrent endometrial cancer |
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E.1.1.1 | Medical condition in easily understood language |
Advanced or recurrent cancer of the endometrium (the lining of the uterus) which presents female hormonal receptors. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014733 |
E.1.2 | Term | Endometrial cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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.
Response and progression will be evaluated by the investigator (local review) in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumours (RECIST) committee version 1.0. |
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E.2.2 | Secondary objectives of the trial |
- Assess safety and tolerability of BN83495
- Assess the following parameters of antitumour efficacy:
- Progression Free Survival (PFS): time from randomisation until objective tumour progression or death from any cause
- Clinical Benefit
- Overall Response
- Time to Progression
- Duration of Response
- Overall Survival at 2 years.
The following will be assessed up to the cut-off date of 17 January 2012:
- Quality of life using EuroQoL EQ-5D
- Effect of treatment on age-related frailty using an oncogeriatric assessment in patients > 65 years
- Pharmacodynamic effects of BN83495 on plasma steriod hormone levels in post-menopausal women
- Pharmacokinetic profile of BN83495 in this patient population after repeated daily administration by means of a population PK analysis.
There are a number of exploratory objectives specified in the protocol and will be assessed up to cut off date 17 January 2012. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetic and Pharmacogenomic Testing:
Title, version and date: the same as main study X-55-58064-004
An assessment of genetic polymorphisms in genes which may be involved in
BN83495 drug disposition and/or pharmacological effect will be undertaken using
baseline blood sample.
Pharmacogenomic testing will also be undertaken to identify biomarkers potentially
predictive of response using microarrays, and to evaluate STS gene expression.
This will be assessed on available samples and up to the cut-off date 17 January 2012. |
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E.3 | Principal inclusion criteria |
1. Provision of written informed consent prior to any study related procedures.
2. Post-menopausal or ovariectomised female patients over the age of 18 years with advanced or recurrent endometrial cancer.
3. Histologically confirmed diagnosis of endometrial carcinoma (primary tumour or metastasis).
4. Not eligible for surgery or radiotherapy alone, at Investigator’s discretion.
5. Document 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).
6. 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.
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
8. At least one measurable disease site (RECIST criteria version 1.0)
- minimum indicator lesion size: 20mm (conventional techniques) or 10mm (spiral CT scan)
- target lesions not situated in irradiated area
9. Life expectancy ≥6 months.
10. Adequate organ function as defined by the following criteria:
- Haemogolobin ≥10g/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 aspartate aminotransferase (AST) and serum alanine aminotransferase (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 class II
11. Patients must have recovered from surgery, radiotherapy and toxicities of adjuvant chemotherapy treatment if applicable.
12. Patients must be willing and able to participate in a clinical trial (including the completion of all necessary study procedures).
13. Patients must be able to swallow oral medication. |
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E.4 | Principal exclusion criteria |
1. Use of any investigational agent in the 4 weeks prior to enrolment in this study
2. 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.
3. Known central nervous system (CNS) metastases
4. Ongoing cardiac dysrhythmias of NCI-CTC adverse event (AE) grade ≥2, or atrial fibrillation of any grade, or QT interval corrected for heart rate using Fridericia's formulas (QTcF) interval >460 msec
5. Patients with contraindications to MA including hypersensitivity to one of the components 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 Investigator’s discretion
6. Concomitant use of systemic carbonic anhydrase II inhibitors (e.g. acetazolamide, dichlorphenamide, methazolamide).
7. History of hypersensitivity to BN83495 or drugs with a similar chemical structure.
8. Likely to require treatment during the study with drugs that are not permitted by the study protocol (see Section 9.7).
9. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of patients who have neither progressed nor died after 6 months of treatment.
Response and progression will be evaluated by the Investigator (local review) using the international criteria proposed by the RECIST committee (version 1.0). Tumour response will be evaluated every 8 weeks. All responses will be confirmed ≥4 weeks after initially evidenced. Additional blinded central review of responses will be performed up to the cut-off date 17 January 2012.
In addition, there is a number of secondary efficacy endpoints and evaluations detailed in the protocol. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Efficacy Endpoints:
1. The following tumour-related endpoints will be evaluated :
• Progression Free Survival
• Clinical benefit
• Overall response
• Time to progression
• Duration of response
2. Overall Survival at 2 years after the last patient randomised (03 June 2011).
3. Quality of life
4. Age-related frailty
5. Pharmacodynamics: the effects of BN83495 on plasma levels of oestrone (E1), oestrone sulphate (E1S), oestradiol (E2), androstenedione (adione), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), androstenediol (adiol) and testosterone will be assessed. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary efficacy endpoints will be assessed according to the protocol defined timepoints. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tumour Assessment via CT scan/MRI |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Moldova, Republic of |
Russian Federation |
Ukraine |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will be considered to have finished at the end of study visit of the last patient. Patients will continue on study treatment until objective tumour progression or 2 years after the last patient randomised (03 June 2011), withdrawal or death. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |