A Phase II, single-arm study of orally administered BEZ235 as second-line therapy in patients with advanced endometrial carcinoma

• Register: EUCTR
• Last refreshed on: 10 February 2014
• Main ID: EUCTR2010-024396-12-IT
• Date of registration: 05/01/2012
• Prospective Registration: No
• Primary sponsor: NOVARTIS FARMA
• Public title: A Phase II, single-arm study of orally administered BEZ235 as second-line therapy in patients with advanced endometrial carcinoma
• Scientific title: A Phase II, single-arm study of orally administered BEZ235 as second-line therapy in patients with advanced endometrial carcinoma
• Date of first enrolment: 13/04/2011
• Target sample size: 140
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-024396-12
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: Single blind: Double blind: Parallel group: no Cross over: no Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other: Number of treatment arms in the trial: 1

Countries of recruitment

Czech Republic, Italy, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Patient written informed consent obtained prior to any screening procedures 2. Patient is a female = 18 years at the day of consenting to the study 3. 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 • all of the following histological types are eligible: endometrioid, papillary serous, clear cell, papillary endometrioid, mucinous, and adeno-squamous • confirmation that the specimen has been collected by the courier service and will be sent to the Novartis-designated lab (e.g., tracking number of courier service) must be communicated to the sponsor prior to enrolling the patient into the treatment phase of the trial 4. Patient has experienced objective progression of disease on or after first-line antineoplastic treatment for advanced or metastatic endometrial carcinoma as defined by the investigator. One prior line of anti-neoplastic treatment is defined as: • First-line treatment for advanced disease including at least one cytotoxic agent. • Any adjuvant treatment is generally not considered a prior line of treatment unless the recurrence occurred while on adjuvant chemotherapy or = 6 months since the last administration of adjuvant chemotherapy (with the exception of endocrine treatments), • Any prior hormonal treatment is not considered a line of treatment in any setting. 5. Patient has recovered (to grade = 1) from all clinically significant toxicities related to prior antineoplastic therapies with the exception of alopecia and bone marrow and organ functions (described separately) 6. Patient has at least one measurable lesion as per RECIST criteria. Lesions in previously irradiated areas should not be considered measurable, unless they have clearly progressed since the radiotherapy. 7. 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). 8. Patient has adequate bone marrow and organ function as defined by the following laboratory values: • Absolute Neutrophil Count (ANC) = 1.0 x 109/L • Platelets = 100 x 109/L • Hemoglobin = 9.0 g/dL • INR = 2 • Serum Creatinine = 1.5 x ULN • Serum Bilirubin = 1.5 x ULN (in patients with known Gilbert Syndrome, total bilirubin = 3 x ULN, with direct bilirubin = 1.5 x ULN) • AST and ALT = 3 x ULN or = 5.0 x ULN if liver metastases are present • Fasting plasma glucose (FPG) = 140 mg/dL (= 7.8 mmol/L) • HbA1c = 8 %
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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 pericarditis9. 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. 15. Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular) are allowed. 16. Patient is currently being treated with any of the following drugs: • Moderate and strong inhibitors or inducers of CYP3A4/5 (see Appendix 1) • Drugs with known risk to induce Torsades de Pointes (see Appendix 3) • Warfarin or coumarin analogues • LHRH agonists17. 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 concur

Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Patients who have experienced progression of disease after first-line antineoplasic treatment of advanced endometrial carcinoma
MedDRA version: 14.1 Level: LLT Classification code 10014745 Term: Endometrial carcinoma metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: BEZ235
Product Code: BEZ235
Pharmaceutical Form: Powder for oral suspension
CAS Number: 1028385-32-1
Current Sponsor code: BEZ235
Concentration unit: mg milligram(s)
Concentration number: 200-

Product Name: BEZ235
Product Code: BEZ235
Pharmaceutical Form: Powder for oral suspension
CAS Number: 1028385-32-1
Current Sponsor code: BEZ235
Concentration unit: mg milligram(s)
Concentration number: 400-

Primary Outcome(s)

Primary end point(s): - ORR per RECIST in patients with PIK3CA mutation and/or PTEN gene mutation and/or PTEN negative by IHC (less than 10% staining) - ORR per RECIST in all patients

Main Objective: • 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.

Secondary Objective: • 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

Secondary ID(s)

2010-024396-12-CZ

CBEZ235C2201