| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Endometrial cancer, advanced, recurrent or metastatic |
|
| E.1.1.1 | Medical condition in easily understood language |
| special type of gynecologic cancer that arises from the endometrium, or lining, of the uterus |
|
| 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 | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014741 |
| E.1.2 | Term | Endometrial cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014740 |
| E.1.2 | Term | Endometrial cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| Compare the overall survival (OS) of patients treated with AEZS-108 to the overall survival of patients treated with doxorubicin |
|
| E.2.2 | Secondary objectives of the trial |
Compare efficacy based on progression-free survival (PFS), overall response rate (ORR), and clinical benefit rate (CBR). Compare safety. Determine the impact of these regimens on patient-reported quality of life.
Sub-study (selected study sites only): Assess pharmacokinetics of AEZS-108, doxorubicin, and doxorubicinol.
Assess acute effects of AEZS-108 and doxorubicin on electrocardiographic parameters |
|
| 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 |
Randomized controlled study comparing AEZS‑108 with doxorubicin as second line therapy for locally advanced, recurrent or metastatic endometrial cancer
Pharmacokinetic sub-study in patients treated with AEZS-108, Version 0, date: 2013-05-02
|
|
| E.3 | Principal inclusion criteria |
1. Woman ≥ 18 years of age
2. Histologically confirmed endometrial adenocarcinoma of any subtype.
a) Endometrioid carcinoma
i. Variant with squamous differentiations
ii. Villoglandular variant
iii. Secretory variant
iv. Ciliated cell variant
b) Mucinous adenocarcinoma
c) Serous adenocarcinoma
d) Clear cell adenocarcinoma
e) Mixed cell adenocarcinoma
f) Squamous cell carcinoma
g) Transitional cell carcinoma
h) Small cell carcinoma
i) Undifferentiated cardinoma
3. Advanced (FIGO stage III or IV), recurrent or metastatic disease.
4. Measurable or non-measurable disease that has progressed since last treatment.
5. Patients with advanced, recurrent or metastatic endometrial cancer who have received one chemotherapeutic regiment with platinum and taxane (either as adjuvant or as first line treatment) and who have progressed.
6. Availability of fresh or archival FFPE tumor specimens for analysis of LHRH receptor expression. |
|
| E.4 | Principal exclusion criteria |
1. Eastern Cooperative Oncology Group (ECOG) performance status > 2
2. Inadequate hematologic, hepatic or renal function
- thrombocyte count: < 100 x 109/L;
- absolute neutrophil count (ANC): < 1.5 x 109/L;
- hemoglobin: < 5.6 mmol/L (< 9 g/dL);
- ASAT, ALAT, AP: > 2.5 times upper limit of normal range (ULN) (> 5x ULN if clearly related to liver metastases);
- creatinine, bilirubin: > 1.5 x ULN
3. Red blood cell transfusion within 2 weeks prior to anticipated start of study treatment.
4. History of myocardial infarction, acute inflamatrory heart disease, unstable angina, or uncontrolled arrhythmia within the past 6 months.
5. Impaired cardiac function defined as left ventricular ejection fraction (LVEF) < 50 % (or below the study site's lower limit of normal) as measured by MUGA or ECHO.
6. Concomitant use of prohibited therapy (as specified in Section 6.3.2).
7. Chemo-, immune-, or hormonetherapy within 5 elimination half life times or 4 weeks prior to randomization, whichever is the shorter. Radiotherapy (including pre- or post-operative brachytherapy) within 4 weeks prior to randomization.
8. Previous anthracycline-based chemotherapy (daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone and valrubicin), in any formulation.
9. Anticipated ongoing concomitant anticancer therapy during the study.
10. History of serious co-morbidity or uncontrolled illness that would preclude study therapy, such as active tuberculosis or any other active infection.
11. Brain metastasis, leptomeningeal disease.
12. Pregnant or lactating female or female of child-bearing potential not employing adequate contraception. Women of childbearing potential must agree to employ adequate contraception until 6 months after the last dose of study drug defined as
- complete abstinence Note: acceptable only as “true abstinence”, i.e. when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence, (e.g.,calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception).;
- any intrauterine device (IUD) with published data showing that the lowest expected failure rate is < 1 % per year; or
- any other methods with published data showing that the lowest expected failure rate is less than 1 % per year.
13.Subjects with known hypersensitivity to peptide drugs, including
LHRH agonists
Lack of suitability for the trial:
22. Malignancies arising from the uterine Cervix
23. Uterine sarcomas or mixed epithelial and mesenchymal tumors including carcinosarcoma, adenosarcoma, or carcinofibroma
14. Receipt of 2 or more prior cytotoxic chemotherapy regimens for advanced, recurrent, or metastatic endometrial cancer.
15. Prior treatment with AEZS-108.
16. Use of LHRH agonist or antagonist treatment within 6 months prior to randomization.
17. Malignancy within last 5 years except non-melanoma skin cancer.
18. Any concomitant disease or condition which would interfere with the subjects’ proper completion of the protocol assignment.
19. Concomitant or recent treatment with other investigational drug (within 4 weeks or 5 elimination half life times prior to anticipated start of study treatment).
Administrative reasons:
20. Lack of ability or willingness to five informed consent.
21. Anticipated non-availability for study visits/procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Overall survival (primary efficacy endpoint).
2a. Efficacy: Progression-free survivall (PFS), overall response rate (ORR = CR + PR), and a clinical benefit rate (CBR) will be evaluated as CR + PR + SD for at least 3 months.
2b. Safety: adverse events, clinical laboratory, ECG and LVEF.
2c. Quality of Life: EORTC QLQ30 + QLQ-EN24 questionnaires.
Pharmacokinetic and electrocardiographic parameters of the PK sub-study. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of the primary efficacy variable will be based on the ITT population. The final overall survival analysis, which is event-based, will be conducted after approximately 384 randomized patients have died. |
|
| E.5.2 | Secondary end point(s) |
Efficacy based on progression-free survival (PFS), overall response rate (ORR), and clinical benefit rate (CBR).
Safety: adverse events, clinical laboratory and LVEF.
Quality of Life: EORTC QLQ30 + QLQ-EN24 questionnaires. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of the primary efficacy variable will be based on the ITT population. The final overall survival analysis, which is event-based, will be conducted after approximately 384 randomized patients have died. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 50 |
| 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 |
| Austria |
| Belarus |
| Belgium |
| Bosnia and Herzegovina |
| Bulgaria |
| Canada |
| Czech Republic |
| Denmark |
| Germany |
| Ireland |
| Israel |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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 |
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