| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Postmenopausal women with HR+/HER2- MBC who have been scheduled
5 years of ET in the adjuvant setting as treatment for early disease and
remained disease free for >12 months after these 5 years, or have "de
novo" metastatic disease. Patients who by own decision have stopped
treatment after 3 years, can be included if they have remained free of
disease 3 years after discontinuing the endocrine therapy. |
|
| E.1.1.1 | Medical condition in easily understood language |
Postmenopausal women presenting with HR-positive/HER2-negative
MBC who have been planned with 5 years of ET after surgery or patient
who have newly diagnosed with metastatic breast cancer. |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic 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 |
To compare the efficacy of fulvestrant in combination with palbociclib versus fulvestrant plus placebo in terms of the rate of Progression-Free Survival (PFS) at 1 year in postmenopausal women with HR-positive/HER2-negative metastatic breast cancer previously treated with endocrine therapy for at least 5 years and remaining disease free for more than 12 months following its completion or have de novo metastatic disease. Patients that have been scheduled 5 years with
adjuvant endocrine therapy and stopped treatment, by patient's own
decision, after completing at least 3 years of treatment, can be also be
included as long as they have remained free of disease 3 years after
discontinuing the endocrine therapy. |
|
| E.2.2 | Secondary objectives of the trial |
To compare other efficacy measures between the treatment arms.
To compare safety and tolerability between the treatment arms.
To compare health related quality of life between the treatment arms. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study.
2. Availability of a tumor tissue sample, archival (primary tumour) or from the metastatic lesions (preferable) for the central ER, PgR and HER2 testing.
3.Histological/cytological confirmation of breast cancer with evidence of metastatic disease (loco-regional or distant), not amenable to resection or radiation therapy with curative intent.
4. Documented positive hormone receptor status (>/=1% of tumour cells with oestrogen receptor [ER] and/or progesterone receptor [PgR] expression) based on central testing on the most recent tumour biopsy.
5. Documented HER2-negative tumour based on central testing on the most recent tumour biopsy. HER2-negative tumour is determined as immunohistochemistry score 0/1+ or negative by in situ hybridization (FISH/CISH/SISH) defined as a HER2/CEP17 ratio <2 or for single probe assessment a HER2 copy number <4.
6. Patients must have received at least 5 years of endocrine therapy in the adjuvant setting as treatment for early disease and remained disease free for more than 12 months following its completion or have de novo metastatic disease. Patients that have been scheduled 5 years with
adjuvant endocrine therapy and stopped treatment, by patient's own
decision, after completing at least 3 years of treatment, can be also be
included as long as they have remained free of disease 3 years after
discontinuing the endocrine therapy.
7. Patients must have at least one lesion (measurable and/or
nonmeasurable) that can be accurately assessed at baseline and is
suitable for repeated assessment by CT, MRI, plan x-ray or physical
examination. Clinical lesions will only be considered measurable when
they are superficial and ≥10mm diameter as assessed using callipers
(e.g. skin nodules). Patients with bone-only disease must have a lytic or
mixed (lytic + blastic) lesion, which has not been previously irradiated
and can be accurately assessed by CT/MRI according to RECIST version
1.1.
8. Postmenopausal patient, defined as a woman fulfilling any one of the following criteria (based on the NCCN definition of menopause [National Comprehensive Cancer Network 2008]):
-Prior bilateral oophorectomy.
- Age >60 years.
- Age equal to or <60 years and with amenorrhea for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle stimulating hormone and estradiol in the postmenopausal range.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.
10. At least 18 years of age.
11. Life expectancy equal to or >12 weeks.
12. Adequate organ and bone marrow function:
ANC equal to or > 1,500/mm3 (1.5x109/L);
- Platelets equal to or >100,000/mm3 (100x109/L);
- Haemoglobin (Hgb) equal to or > 9g/dL (90g/L);
- Serum creatinine equal or < 1.5xUpper Limit of Normal (ULN) or estimated creatinine clearance equal to or > 60ml/min as calculated using the method standard for the institution;
- Total serum bilirubin equal or < 1.5xULN (<3xULN if Gilbert´s disease);
- AST and/or ALT equal or < 3xULN (equal or <5xULN if liver metastases present);
-Alkaline Phosphatase (AP) equal to or < 2.5xULN (equal to or < 5xULN if bone or liver metastases present).
13. Patients consent to biological sample provision for biomarker exploratory analysis.
14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1.Prior systemic therapy for metastatic disease. Note: patients with a local recurrent disease treated with surgery (R0) and receiving a second hormonal adjuvant therapy for five years will be allowed, provided they have remained disease free for more than 12 months following its completion.
2. Have "de novo" locally advanced disease.
3. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers, and drugs that are known to prolong the QT interval.
4. Presence of life-threatening metastatic visceral disease, defined as extensive hepatic involvement, or any degree of brain or leptomeningeal involvement (past or present), or symptomatic pulmonary lymphangitis spread, or any known bone marrow infiltration due to breast cancer. Patients with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not significantly compromised as a result of disease.
5. Treatment with a non-approved or experimental drug within 4 weeks before randomization.
6. Prior treatment with any CDK4/6 inhibitor or fulvestrant.
7. Current or prior malignancy within previous 5 years (other than breast cancer or adequately treated basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix).
8. History of:
- Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting factor deficiency) or long-term (>6 months) anticoagulant therapy (other than antiplatelet therapy and low dose dose coumarin
derivatives provided that the International Normalised Ratio (INR) is
less than 1.6).
- Hypersensitivity to active or inactive excipients of fulvestrant, palbociclib/placebo or castor oil.
- Any severe concomitant condition which makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the trial protocol, e.g. uncontrolled cardiac disease or uncontrolled diabetes mellitus.
9. QTc interval > 480msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcaemia, hypokalaemia, hypomagnesaemia).
11. Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of palbociclib, such as history of GI surgery which may result in intestinal blind loops and patients with clinically significant gastro-paresis, short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease or diarrhoea of CTCAE grade > 1.
12. Prior hematopoietic stem cell or bone marrow transplantation.
13. Known human immunodeficiency virus infection.
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Rate of patients free of progression at 1 year assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 by the investigator. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of rate of patients free of progression at 1 year will be carried out when all patients have been randomised and have had a follow-up of at least 12 months. |
|
| E.5.2 | Secondary end point(s) |
- The following efficacy endpoints will be measured:
- Progression-Free Survival (PFS) assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 by the investigator.
- Objective Response Rate (ORR): Complete Response (CR) plus Partial Response (PR) according to RECIST version 1.1.
- Clinical Benefit Rate (CBR): CR plus PR plus stable disease (SD) lasting = or > 24 weeks (+/-2 weeks) according to RECIST version 1.1.
- Overall Survival (OS).
- 1 year and 2 year survival probabilities.
-Safety will be assessed by standard clinical and laboratory tests (haematology, serum chemistry). AEs grade will be defined by the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.0.
-Changes (mean score) and time to deterioration on EORTC QLQ-C30 Global Health Status/QoL and Physical Function and EORTC QLQ-BR23 Breast Module from baseline |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Initially an analysis of PFS was planned when at least 60% of patients have progressed (approximately 114 progression events), however, this analysis was performed together with the primary endpoint analysis ( PFS at 1 year), because this analysis was carried out when 96 PFS events had occurred (50.5% of patients had progressed). An update of PFS will be performed together with the final OS analysis.
|
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 | 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 date of study is the date of the database lock and will be independent of performing the analysis of the exploratory objectives. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 50 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 50 |
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