| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with endocrine-resistant metastatic or locally relapsed, ER+/HER2-negative breast cancer not amenable to treatment with a curative intent enrolled in the AURORA study. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with an estrogen receptor positive and HER2-negative cancer which started in the breast and which now has either re‐appeared or has spread to other organs. |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| Progression-free survival correlated with gene mutations |
|
| E.2.2 | Secondary objectives of the trial |
- Safety and tolerability
- Disease control |
|
| 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 |
- FDG-PET substudy
- Version 1.2, 27May2015 (substudy is part of core trial protocol, section 16.)
- Primary objective: Evaluation if early metabolic response (MR) using FDG-PET/CT is associated with progression free survival
- Secondary objective: Evaluation if early metabolic response (MR) using FDG-PET is associated with disease control rate |
|
| E.3 | Principal inclusion criteria |
- Histologically confirmed breast adenocarcinoma that is metastatic or locally relapsed disease not amenable to curative therapy.
- Female gender
- Age ≥ 18 years
-Postmenopausal, defined as women with:
- Prior bilateral surgical oophorectomy; or
- Amenorrhea and age ≥ 60 years; or
- Age < 60 years and amenorrhea for 12 or more consecutive months in the absence of alternative pathological or physiological cause (including chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and serum estradiol levels within the laboratory’s reference ranges for postmenopausal women.
- Endocrine resistant disease, defined as one of:
- Relapse while on adjuvant endocrine therapy
- Relapse within 12 months after completion of adjuvant endocrine therapy
- Progression of disease under first line endocrine therapy for metastatic and/or loco-regionally advanced breast cancer
Note: Patient may have received one prior chemotherapy for advanced or metastatic breast cancer.
- ER positive tumor and HER2-negative tumor, as assessed locally
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
- Measurable or non-measurable but evaluable disease according to RECIST 1.1. Bone only disease is allowed. Previously irradiated lesions are deemed measurable only if progression is documented at the site after completion of radiation.
- Written Informed Consent (IC) for screening procedures and trial participation must be signed and dated by the patient and the Investigator prior to screening.
- Written informed consent to participate in the AURORA program of BIG.
- The patient has been informed of and agrees to data transfer and handling, in accordance with national data protection guidelines.
- Life expectancy >3 months.
- Hematologic status:
- Absolute neutrophil count ≥ 1.5 × 109/L (without growth factor support),
- Platelet count ≥ 100 × 109/L (no transfusion allowed within 2 weeks prior to asessment),
- Hemoglobin ≥ 9 g/dL (transfusion permitted)
- Hepatic status:
- Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known Gilbert’s syndrome, a higher serum total bilirubin (< 3 × ULN) is allowed.
- AST and ALT ≤ 2.5 × ULN; if the patient has liver metastases, ALT and AST must be ≤ 5 × ULN.
- Glucose in normal range, or well-controlled diabetes defined as an HbA1c level ≤ 7.5%.
- Renal status:
- Creatinine ≤ 1.5 ×ULN or creatinine clearance > 60 ml/min
- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulant
- Ability to swallow oral medication |
|
| E.4 | Principal exclusion criteria |
- Prior use of fulvestrant or any CDK inhibitor.
- More than one prior line of chemotherapy for metastatic or locally relapsed disease.
- Previous or current non-breast malignancies within the last 5 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin.
- Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy,) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before enrollment.
- Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (NYHA functional classification ≥III, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
- QTc exceeding 480msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
- Uncontrolled electrolyte disorders that can reinforce the QT-prolonging effect of the drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
- Known history of HIV seropositivity. HIV screening is not required at baseline.
- Uncontrolled diabetes defined as HbA1c level > 7.5%.
- Concurrent disease or familial, sociological or geographical condition that would make the patient inappropriate for trial participation or any serious medical disorder that would interfere with the patient’s safety.
- Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of Informed Consent.
- Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant
- Treatment with an investigational agent in the 4 weeks before enrollment.
- Concurrent treatment with any of the drugs not permitted, i.e. strong CYP3A inhibitors/inducers and drugs known to cause QT interval prolongation
- Adverse events (except alopecia) from previous systemic cancer therapy, radiotherapy or surgery have not recovered to CTCAE v4.0 grade 1 or resolved prior to enrollment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival correlated with gene mutations assessed both in ctDNA as well as in tumor tissue and two recently developed gene signatures. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time from treatment initiation until documented disease progression according to RECIST 1.1 criteria or death, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
- Safety and tolerability (as documented according to NCI CTCAE v4.0)
- Disease control (based on RECIST 1.1 criteria) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety and tolerability:
Adverse events (AE) will be collected using CTCAE v4.0.
Disease Control:
Best overall response of complete response (CR) or partial response (PR), or stable disease (SD) lasting for at least 24 weeks, measured from enrollment until first documentation of progressive disease. |
|
| 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 | No |
| 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) | 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 | No |
| 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 | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
Individual patients’ trial participation ends with the End of Treatment (EoT) visit, or a maximum of 12 months after EoT in the absence of tumor progression.
Clinical visits are expected to span approximately 36 months after enrollment of the first patient. The final trial analysis is expected 30-36 months after the inclusion of the first patient under Amendment 1. |
|
| 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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