| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with hormonal receptor positive and HER2 negative MBC who are resistant to prior NSAI therapy. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with hormonal receptor positive and HER2 negative metastatic breast cancer who are resistant to prior non-steroidal aromatase inhibitors therapy. |
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| 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 | 19.0 |
| 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 |
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| 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 demonstrate that palbociclib in combination with fulvestrant is superior to capecitabine in prolonging Progression-Free Survival (PFS) in postmenopausal women with ER positive/HER2 negative MBC whose disease was resistant to non-steroidal aromatase inhibitors, regardless of the ESR1 mutational status. - To
demonstrate that palbociclib in combination with endocrine therapy (exemestane or fulvestrant) is superior to capecitabine in prolonging PFS in postmenopausal women with ER positive/HER2 negative MBC whose disease was resistant to non-steroidal aromatase inhibitors and whose tumor had estrogen receptor (ESR1) mutational status as wild type at study entry. ESR1 mutational status will be determined by circulating free DNA (cDNA) and will be prospectively determined before the interims or final analyses. Patient tumor ESR1 mutational status will be blinded to patients, investigators and study team.
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| E.2.2 | Secondary objectives of the trial |
- To demonstrate that palbociclib in combination with endocrine therapy (exemestane or fulvestrant) is superior to capecitabine in prolonging PFS in postmenopausal women with ER positive/HER2 negative MBC whose disease was resistant to non-steroidal aromatase inhibitors regardless of ESR1 mutational status at study entry. - To demonstrate that palbociclib in combination with fulvestrant is superior to capecitabine in prolonging Overall Survival (OS) in postmenopausal women with ER positive/HER2 negative MBC whose disease was resistant to
non-steroidal aromatase inhibitors. - To demonstrate... Please, to see all Secondary Objectives, refer to the Protocol Version 5.0 of 9 March 2016.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.The patient has signed the informed consent document.
2.Females with histologically confirmed MBC whose disease is resistant to previous non-steroidal aromatase inhibitors (letrozole or anastrozole), defined as:
- Recurrence while on or within 12 months after the end of adjuvant treatment with NSAI or
- Progression while on or within 1 month after the end of treatment with NSAI for advanced disease.
3.Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or first line therapy for MBC.
4.It is not mandatory to have letrozole or anastrozole as the most recent treatment before randomization but progression of the MBC documented during receipt of the most recent systemic therapy before randomization should be documented.
5.Hormonal receptor positive (HR+) breast cancer based on local laboratory determination. HR+ defined as > or = 1% positive cells by IHC for ER and/or PgR.
6.Documented HER2 negative breast cancer based on local laboratory determination on most recent tumor biopsy. HER2 negative tumor is determined according to the most current recommendations of ASCO/CAP guidelines (2013), as IHC score 0 or 1+ or negative by ISH (FISH/CISH/SISH) defined as a HER2/CEP17 ratio < 2 with an average HER2 copy number <4.0, or for single probe assessment a HER2 copy number < 4.
7.Measurable disease or at least one bone lesion, lytic or mixed (lytic+blastic), which has not been previously irradiated and is assessable by CT/MRI in the absence of measurable disease according to RECIST 1.1 criteria.
8.Patient is at least 18 years of age.
9.Eastern Cooperative Oncology Group (ECOG) Performance Status < or = 1.
10.Life expectancy > or = 12 weeks.
11.Adequate organ and bone marrow function defined as follows:
- ANC > or = 1,500/mm3 (1.5x109/L)
- Platelets > or = 100,000/mm3 (100x109/L)
- Hemoglobin > or = 9g/dL (90g/L)
- Serum creatinine < or = 1,5xULN or estimated creatinine clearance > or = 60 mL/min as calculated using the standard method for the institution
- Total serum bilirubin < or = 1,5xULN (< or = 3.0xULN if Gilbert´s disease)
- AST and/or ALT < or = 3.0xULN (< or = 5.0xULN if liver metastases present)
- Alkaline phosphatase < or = 2.5xULN (< or = 5.0xULN if bone or liver metastases present)
12.Postmenopausal women defined as women with: -Prior bilateral surgical oophorectomy, or -Age > 60 years
-Age < 60 year and medically confirmed post-menopausal status defined as spontaneous cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause or follicle-stimulating hormone (FSH) and estradiol blood levels in their respective postmenopausal ranges
13.Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade < or = 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion).
14.Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. |
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| E.4 | Principal exclusion criteria |
1. Have received more than 1 prior chemotherapy regimen for MBC. NOTE: Other previous anticancer endocrine treatments for advanced disease are allowed.
2. Patients with advanced, symptomatic, visceral spread that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis and over 50% liver involvement).
3. 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 (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
4. Prior treatment with any CDK4/6, mTOR or PI3K inhibitor [any agent whose mechanism of action is to inhibit the PI3 kinase-mTOR pathway] or capecitabine.
5.
a) Patients included in Cohort 1: Prior treatment with exemestane in the metastatic setting. If the patient has received exemestane in the adjuvant setting and developed MBC, she will be eligible for the study provided: - She has received letrozole/anastrozole as first-line MBC and progressed. - At least 1 year has elapsed since the end of adjuvant exemestane treatment. b) Patients included in Cohort 2: Prior treatment with fulvestrant in the metastatic setting. If the patient has received fulvestrant in the adjuvant setting and developed MBC, she will be eligible for the study provided: - She has received letrozole/anastrozole as first-line MBC and progressed. - At least 1 year has elapsed since the end of adjuvant fulvestrant treatment.
6. Patients treated within the last 7 days prior to randomization with:
- Food or drugs that are known to be CYP3A4 inhibitors
- Drugs that are known to be CYP3A4 inducers
- Drugs that are known to prolong the QT interval
7. Major surgery, chemotherapy, radiotherapy, any investigational agent or other anti-cancer therapy within 4 weeks before randomization. Patients who received prior radiotherapy to > or = 25% of bone marrow are not eligible independent of when it was received.
8. Diagnosis of any other malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
9. QTc > 480msec (based on the mean value of the triplicate ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
......... 13. Known hypersensitivity to exemestane, palbociclib, capecitabine, fulvestrant or any of their excipients. 15.Only for patients in Cohort 2 any of the following contraindications for treatment with fulvestrant: Bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting factor deficiency) or long-term anticoagulant therapy (other than antiplatelet therapy and low dose warfarin). Please, to see all Principal exclusión criteria, refer to the Protocol Version 5 of 9 March 2016. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| - Progression-Free Survival (PFS), based on the investigators assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Approximately 28 months from the start of cohort 2 study randomization. |
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| E.5.2 | Secondary end point(s) |
- Objective Response Rate (ORR): Complete Response (CR) plus Partial Response (PR) divided by the number of patients randomized with measurable disease.
- Clinical Benefit Rate (CBR): CR plus PR plus stable disease lasting more than 24 weeks divided by all randomized patients (ITT population).
- Response Duration (RD).
- Overall Survival (OS).
- 1 year and 2 year survival probabilities.
- Safety will be assessed by standard clinical and laboratory tests (hematology, serum chemistry). Adverse events grade will be defined by the NCI CTCAE v4.0. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- OS approximately 50 months from the start of cohort 2 study randomization.
- Efficacy endpoints will be assessed at the end of the study.
- Safety will be assessed along the cycles. |
|
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 50 |
| 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 | No |
| 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 |
| Austria |
| Hungary |
| Israel |
| Latvia |
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| 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
|
| Last visit last active patient in the study. |
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| 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 | 7 |
| 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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