| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Metastatic Breast Cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| 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 |
| The primary objective of this study is to assess the efficacy of 2 dosing regimens of BIIB021 in combination with exemestane in women whose HR+ breast cancer had progressed following treatment with a nonsteroidal AI. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of this study is to evaluate the safety and tolerability of BIIB021 in combination with exemestane in this study population. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of enrollment or at the timepoint specified in the individual eligibility criterion listed:
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
2. Age ≥18 years at the time of informed consent or the age of consent in accordance with national regulations, whichever is higher.
3. Must have histologically or cytologically confirmed estrogen receptor-positive or progesterone receptor-positive, incurable, locally advanced, or metastatic breast cancer.
• If available, pre-existing formalin-fixed and paraffin-embedded (FFPE) tumor tissue must be submitted to Biogen Idec before study completion, but not necessarily prior to enrollment (see Study Reference Manual).
4. Must have disease progression during treatment with a nonsteroidal AI for locally advanced or metastatic disease, or relapse during treatment or within 12 months of discontinuation of treatment in the adjuvant setting.
5. Must be a postmenopausal female defined as ≥60 years old, OR age ≥45 years with amenorrhea for ≥12 months with an intact uterus AND follicle stimulating hormone levels within postmenopausal range, OR prior bilateral oophorectomy.
6. Expected survival time of at least 3 months in the opinion of the Investigator.
7. Must have measurable or evaluable disease.
• Measurable disease is defined as ≥1 lesion with a diameter of ≥10 mm (lesion must be measurable in ≥1 dimension, with the longest diameter to be recorded). See Section 13.1.1 for details.
• Evaluable disease is defined as bone lesions evaluable by plain X ray, CT scan, or MRI. Lesions identified only by radionuclide bone scan are not allowed.
• The target lesion(s) must not have been previously irradiated (newly arising lesions in previously irradiated areas are acceptable).
• The following are not considered measurable or evaluable disease: leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast cancer, lymphangitis cutis/pulmonitis, cystic lesions, and abdominal masses that cannot be reproducibly measured and followed by CT or MRI.
8. One prior chemotherapy regimen for advanced metastatic breast cancer is allowed. Must be at least 2 weeks since final treatment, and the subject must be recovered to baseline or ≤Grade 1 toxicity from prior treatment.
• Prior chemotherapy in the adjuvant and/or neoadjuvant setting is allowed.
9. Prior radiotherapy is allowed. Must be at least 2 weeks since treatment and the subject must be recovered to baseline or ≤ Grade 1 toxicity from prior treatment. Exceptions are as follows:
• Strontium 90 (or other radiopharmaceutical) within previous 3 months is not allowed.
• Sites of measurable disease must be outside the radiotherapy port.
10. If the subject is taking bisphosphonates for bone metastases, bisphosphonate therapy must be established for at least 3 months. Concurrent initiation of bisphosphonates will be allowed if the subject has soft tissue or visceral metastases as the measurable or evaluable target lesion.
11. Must be able to swallow and retain oral medication.
12. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 (Appendix A).
13. Required laboratory values:
• ANC ≥1 × 103 cells/mm3, platelet count 75 × 103 cells/mm3, hemoglobin ≥90 g/L (≥9 g/dL).
• Bilirubin ≤3 x upper limit of normal (ULN) (unless due to Gilbert’s syndrome), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥5 ≥ULN.
• Serum creatinine ≤177 μmol/L (≤2.0 mg/dL).
• International Normalized Ratio (INR)≤1.5, except in subjects who are currently on anti coagulation therapy and their most recent thrombotic event occurred >3 months prior to Day 1, then INR≤3.5.
• Glucose ≥3.3 mmol/L (≥60 mg/dL), sodium ≥130 mmol/L, calcium ≥2.0 mmol/L (≥8 mg/dL).
• Plasma cortisol and adrenocorticotropic hormone (ACTH) levels that are not suggestive of adrenal insufficiency unless on replacement therapy for known adrenal insufficiency.
14. Electrocardiogram (ECG) with QTc of ≤470 msec and no clinically significant findings.
|
|
| E.4 | Principal exclusion criteria |
Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of enrollment or at the timepoint specified in the individual criterion listed:
1. HER2 overexpressing tumor (immunohistochemistry [IHC] 3+ or fluorescence in situ hybridization [FISH]+).
2. Life-threatening metastatic visceral disease.
3. History of central nervous system (CNS) metastasis.
4. History of prior malignancies within the past 5 years with the exception of curatively treated basal or squamous cell carcinomas of the skin or carcinoma in situ of the cervix.
5. Previous treatment with exemestane.
6. Previous treatment with an Hsp90 inhibitor.
7. Other concurrent hormonal therapy except for the following: steroids for adrenal failure, hormones for nondisease-related conditions (i.e., insulin for diabetes or Synthroid® for hypothyroidism), intermittent dexamethasone as an antiemetic.
8. Use of medications that may affect the metabolism of BIIB021 within 14 days of the first dose of study treatment
9. Use of medications that may affect the metabolism of exemestane, such as potent inducers of cytochrome p450 3A4 (CYP3A4), within 14 days of the first dose of study treatment
10. Use of proton pump inhibitors within 7 days of the first dose of study treatment. H2 antagonists, except cimetidine, will be allowed.
11. Active bacterial or viral infection requiring concurrent treatment.
12. Known history of or positive test result for hepatitis B or C.
13. Known history of or positive test result for human immunodeficiency virus (HIV).
14. Uncontrolled, severe medical illness, which in the opinion of the Investigator and/or Sponsor could compromise protocol objectives.
15. History of gastrectomy or major surgery to small intestine.
16. Chronic diarrhea (excess of 2 to 3 stools/day above normal frequency).
17. Major surgery within 28 days of first study treatment.
18. Conditions that may predispose subjects to seizures:
• History of seizure, previous significant head trauma (e.g., associated with loss of consciousness for more than 5 minutes), abrupt discontinuation of benzodiazepines, or use of potentially epileptogenic medications
19. Drug or alcohol abuse.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is progression-free survival (PFS), which is defined as the time interval from the date of randomization until disease progression or death, whichever occurs first. |
|
| 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 | Yes |
| 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) | 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 4 |
| 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
|
| The end of study is defined as the date of the last clinic visit for the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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