E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients who have experienced progression of disease after first-line antineoplasic treatment of advanced endometrial carcinoma |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 13.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014745 |
E.1.2 | Term | Endometrial carcinoma metastatic |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To demonstrate the efficacy of BEZ235 as measured by Overall Response Rate (ORR) per RECIST (Novartis guidelines based on RECIST Version 1.1) in patients with advanced endometrial carcinoma who exhibit PI3K pathway activation defined as the presence of a PIK3CA and/or PTEN mutation and/or PTEN negative by IHC (less than 10% staining).
• To demonstrate the efficacy of BEZ235 as measured by Overall Response Rate (ORR) per RECIST in all patients enrolled in the study.
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E.2.2 | Secondary objectives of the trial |
• To determine the efficacy of BKM120 as measured by Objective Response • To determine Progression Free Survival (PFS)
• To determine the efficacy of BEZ235 as measured by Overall Response Rate (ORR) per RECIST in patients with advanced endometrial carcinoma who exhibit a non-activated PI3K pathway
• To determine the Disease Control Rate (DCR)
• To determine Time to Response (TTR)
• To determine Duration of Response
• To assess Overall Survival (OS)
• To evaluate the safety of BEZ235
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patient is a female ≥ 18 years at the day of consenting to the study
• Patient has a histologically confirmed diagnosis of advanced endometrial carcinoma with available tissue specimen, either archival tissue (one block or a minimum of 20 unstained slides) or fresh formalin fixed tumor biopsy, for identification of PI3K pathway activation
• Patient has experienced objective progression of disease on or after first-line anti-neoplastic treatment for advanced or metastatic endometrial carcinoma
• Patient has recovered (to grade ≤ 1) from all clinically significant toxicities related to prior antineoplastic therapies (with the exception of alopecia) and has adequate bone marrow and organ functions
• Patient has at least one measurable lesion as per RECIST
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 which is not declining during the last 2 weeks before the signature of the main study Informed Consent Form (S-ICF).
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E.4 | Principal exclusion criteria |
1. Patient has received previous treatment with PI3K and/or mTOR inhibitors
2. Patient has received more than one line of antineoplastic treatment for advanced or metastatic disease (for definition of prior lines of therapy please refer to inclusion criterion 4)
3. Patient has active uncontrolled or symptomatic CNS metastases
4. Note: Patients with controlled and asymptomatic CNS metastases may participate in this trial. As such, the patient must have completed any prior treatment for CNS metastases > 28 days (including radiotherapy and/or surgery) prior to enrollment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases.
5. Patient has a concurrent malignancy or has had a malignancy in the last 3 years prior to start of study treatment (with the exception of adequately treated basal or squamous cell carcinoma or cervical carcinoma in situ)
6. Patient has received pelvic and/or para-aortic radiotherapy ≤ 28 days or limited filed palliative radiotherapy ≤ 14 days prior to enrollment in this study or has not recovered from side effects of such therapy at the time of initiation of screening procedures.
7. Patient has had major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery
8. Patient has active cardiac disease including any of the following:
• Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
• QTc > 480 msec on screening ECG (using the QTcF formula)
• Unstable angina pectoris
• Ventricular arrhythmias except for benign premature ventricular contractions
• Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
• Conduction abnormality requiring a pacemaker
• Valvular disease with documented compromise in cardiac function
• Symptomatic pericarditis
9. Patient has a history of cardiac dysfunction 10. Family history of congenital long or short QT, or known history of QT/QTc prolongation or Torsade de Point(TdP)
11. Inadequately controlled hypertension(i.e, SBP >180 mmHg or DBP >100mmHg)
12. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea grade ≥ 2, malabsorption syndrome, or small bowel resection)
13. Patient is concurrently using other approved antineoplastic or any investigational agents (hormonal agent included) in the last 30 days prior to start of treatment
14. Patient receiving chronic treatment with systemic steroids or another immunosuppressive agent at start of study treatment..
16. Patient is currently being treated with any of the following drugs:
• Moderate and strong inhibitors or inducers of CYP3A4/5 (Please refer to Appendix 1 for a list of prohibited CYP3A4 inhibitors and inducers)
• Drugs with known risk to induce Torsades de Pointes (see Appendix 3 for a list of prohibited drugs)
• Warfarin or coumarin analogues
• LHRH agonists
17. Patient is consuming Seville oranges, grapefruit, grapefruit hybrids, pummelos and exotic citrus fruits (as well as their juices) during the last 7 days prior to start of treatment. Regular orange juice is permitted
18. Immunocompromised patients, including known seropositivity for HIV (testing is not mandatory)
19. Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment contraindicate her participation in the clinical study (e.g. uncontrolled diabetes, chronic pancreatitis, active chronic hepatitis etc.)
20. Patient is not able to understand or to comply with study instructions and requirements or has a history of non-compliance to medical regimen
21. Patient is a pregnant or nursing (lactating) woman, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum hCG laboratory test (> 5 mIU/mL)
22. Patient is a woman of child-bearing potential, defined as a woman physiologically capable of becoming pregnant, including a woman whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using a double barrier method for birth control throughout the trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR per RECIST* in patients with PI3K pathway activation
ORR per RECIST |
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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 | Yes |
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 | 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) | 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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 | Information not present in EudraCT |
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 |
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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
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The final analysis will occur once at least 140 evaluable patients. Any patients receiving study treatment at that time will continue to receive BEZ235 for as long as they continue to receive benefit in the opinion of the investigator |
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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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |