| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients with hormone receptor positive, HER2 negative, metastatic breast cancer, with or without PI3K activated pathway |
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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 | 10027475 |
| E.1.2 | Term | Metastatic breast 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the efficacy of BEZ235
16-week Progression Free Survival Rate (PFSR) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate additional efficacy parameters
• KM estimates of 16 & 24week PFSR
• Clinical Benefit Rate
• Time to Response
• Duration of Response
• 24-week Progression Free Survival Rate
• Median Progression Free Survival
• Median Overall Survival
• To evaluate safety and tolerability of BEZ235
• Frequency and severity of adverse events
• Abnormal lab values
• Other safety data as considered appropriate
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patient has provided a signed molecular screening and study Informed Consent Form prior to any screening procedure
2. Patient is a female ≥ 18 years of age on the day of consenting to the study (including molecular screening consent)
3. Patient has a histologically and/or cytologically confirmed diagnosis of breast cancer presenting with metastatic disease that is
• hormone receptor positive (based on most recently analyzed biopsy, as documented by a local laboratory); hormone positivity is defined as estrogen receptor and/or progesterone receptor positive, and
• human epidermal growth factor receptor 2 (HER2) negative, as documented by a negative CISH/FISH test or an IHC status of 0, 1+ or 2+ (if IHC 2+, a negative FISH/CISH test is required) (based on most recently analyzed biopsy, as documented by a local laboratory)
4. Patient has a known PI3K activation status (defined by PIK3CA mutation and PTEN mutation/expression) prior to start of treatment and has a PI3K activation status of a stratification group enrolling at the time of start of treatment. For this either most recent archival tissue (preferably: one block or a minimum of 20 unstained slides) or fresh formalin fixed tumor sample is mandatory and must be sent to Novartis or a central laboratory designated by Novartis.
5. Patient has received for metastatic breast cancer at least one prior line of endocrine therapy and at least two and no more than three prior lines of chemotherapy.
Note: A chemotherapy line in metastatic disease is an anticancer regimen that contains at least one cytotoxic chemotherapy agent or a targeted therapy.
If a regimen (endocrine or chemotherapy) was discontinued for a reason other than disease progression and lasted less than 21 days, then this regimen does not count as a prior line.
Prior adjuvant endocrine or chemotherapy will be counted as a prior line for metastatic disease only if the patient had progressed while on adjuvant endocrine or chemotherapy or within 12 months after the last administration of the respective therapy. Sequential neoadjuvant/adjuvant therapy will be counted as one regimen.
6. 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).
7. Patient has objective and radiologically confirmed progression of disease.
8. Patient has at least one measurable lesion as per RECIST.
9. 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).
10. Patient has adequate bone marrow and organ function as shown by:
• Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin (Hgb) ≥ 9.0 g/dL
• INR ≤ 2
• Serum creatinine ≤ 1.5 x ULN
• Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
• AST and ALT ≤ 3 x ULN (or ≤ 5.0 x ULN if hepatic metastases are present)
• Fasting plasma glucose (FPG) ≤ 140mg/dL [7.8 mmol/L]
• HbA1c ≤ 8 %
|
|
| E.4 | Principal exclusion criteria |
1. Patient has received previous treatment with PI3K and/or mTOR inhibitors
2. Patient has active uncontrolled or symptomatic CNS metastases
3. 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).
4. Patient has received wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study drug or has not recovered from side effects of such therapy.
5. Patient has had major surgery within 28 days prior to starting study drug or has not recovered from major side effects of the surgery.
6. Patient has active cardiac disease
7. Patient has a history of cardiac dysfunction
8. Family history of congenital long or short QT, or known history of QT/QTc prolongation or Torsades de Pointes (TdP).
9. Inadequately controlled hypertension (i.e., SBP>180 mmHg or DBP>100mmHg).
10. 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).
11. Patient is concurrently using other approved antineoplastic or any investigational agents (hormonal agent included) in the last 30 days prior to start of treatment.
12. Patient is receiving chronic treatment with systemic steroids or another immuno-suppressive agent at start of study treatment.
13. Patient is being treated at start of study treatment with any of the following drugs:
• Drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A4 including herbal medications (see Appendix 1 for a list of prohibited CYP3A4 inhibitors and inducers)
• Drugs with a known risk to induce Torsades de Pointes (see Appendix 3 for a list of prohibited drugs)
• Warfarin and coumadin analogues
• LHRH agonists
14. 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.
15. Immunocompromised patients, including known seropositivity for HIV (testing is not mandatory)
16. 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.).
17. Patient is not able to understand or to comply with study instructions and requirements or has a history of non-compliance to medical regimen.
18. 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 βhCG laboratory test (> 5 mIU/mL).
19. 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) |
• 16-week Progression Free Survival Rate (PFSR)
• Objective Response Rate
|
|
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
|
| 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
|
| Patients will continue study treatment until disease progression or until any of the study's discontinuation criteria are met. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 |
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