| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hormone receptor-positive/HER2-negative Advanced Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hormone receptor-positive/HER2-negative Advanced 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 | 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 |
| To compare the efficacy, defined as progression-free survival (PFS), of continuation of palbociclib treatment combined with second-line endocrine therapy (fulvestrant or letrozole) versus endocrine therapy in pre- and post-menopausal women with HR-positive/HER2-negative ABC |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the safety and tolerability of interventional arm versus control arm.
• To compare the objective response rate (ORR), the duration of response (DoR), the time to response (TTR), the clinical benefit rate (CBR), the time to progression (TTP), and the overall survival (OS) of interventional arm versus control arm.
• To compare the patient reported global Quality of Life, functioning and symptoms of interventional arm versus control arm.
• To perform subgroup analysis for primary and secondary endpoints in stratified groups of patients.
• To compare the time to first chemotherapy of interventional arm versus control arm.
• To explore correlations between the intrinsic molecular subtypes and efficacy/safety findings.
• To explore potential molecular markers of sensitivity and/or resistance for interventional arm and control arm, according to, but not limited to, the results obtained from the BioPER trial (NCT03184090). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.- Female patients ≥18 years of age.
2.- Pre-menopausal (treated with a LHRH analogue for at least 28 days) or post-menopausal women.
3.- ECOG 0 - 1.
4.- Life expectancy ≥12 weeks.
5.- ABC not amenable to curative treatment.
6.- HR-positive and/or HER2-negative.
7.- Disease progression on first-line combination of palbociclib + endocrine therapy (AI or fulvestrant).
8.- Clinical benefit to a first-line palbociclib-based endocrine regimen.
9.- Previous palbociclib dose: min 100 mg during the last 2 cycles.
10.- Last dose of palbociclib administered not later than 8 weeks and not earlier than 7 days from study entry, (except in the adjuvant setting).
11.- Patients should not have been treated in the advanced setting with at least one of these endocrine therapy options: either fulvestrant or AI.
Note: Patients treated with adjuvant AI with a disease- free interval ≥ 12 months, and with first-line fulvestrant in the metastatic setting, could receive treatment with an AI in the metastatic setting.
12.- Measurable or evaluable disease acc. RECIST v.1.1. Patients with only bone lesions are eligible.
13.- Tumor tissue biopsy (if feasible) from a metastatic site or the primary breast tumor, both at inclusion and after disease progression for exploratory studies. If not feasible, eligibility to be evaluated by Sponsor’s designee.
14.- Patients agree to collection of blood samples (liquid biopsy) at inclusion, after 2 weeks of treatment, and upon progression or study termination.
15.- Adequate organ function.
16.- Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
17.- Patients informed and signed informed consent.
18.- Resolution of all acute toxic effects of prior anti- cancer therapy to grade </= 1 (NCI-CTCAE) v.5.0 (except for alopecia or other toxicities, such as myelosuppression, not considered a safety risk for the patient at investigator's discretion). |
|
| E.4 | Principal exclusion criteria |
1. HR or HER2 unknown disease.
2. HER2-positive disease based on local laboratory results
(performed by IHC / ISH test).
3. Locally ABC candidate for curative treatment.4. Formal contraindication to endocrine therapy defined as visceral crisis and rapidly or symptomatic progressive visceral disease.
5. Prior therapy with any other CDK4/6 inhibitor different from palbociclib.
6. Known active uncontrolled or symptomatic Central Nervous System (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 (e.g., radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization.
7. Patients are currently receiving food or drugs known to be strong inducers or inhibitors of CYP3A4 (see Section 3.5 for details on prohibited medications).
8. Current or prior malignancy which could affect compliance with the protocol or interpretation of results. Patients with curatively- treated non-melanoma skin cancer, non-muscle-invasive bladder cancer, or carcinoma in situ, among others, are generally eligible.
9. No other systemic therapy for metastatic disease including chemotherapy, immunotherapy, targeted therapy (small molecules/ monoclonal antibodies), or endocrine therapy excluding first-line palbociclib-based regimen.
10. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 2 weeks of start of study drug, or patients who have not recovered from the side effects of any major surgery, or patients who may require major surgery during the study.
11. Radiotherapy or limited-field palliative radiotherapy within 7 days prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously irradiated.
12. Use of concurrent investigational agents or other concomitant anticancer therapies.
13. Active bleeding diathesis, previous history of bleeding diathesis, or chronic anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon as it is used as prophylaxis intention).
14. Serious concomitant systemic disorder (e.g., active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator).
15. Unable to swallow capsules or tablets.
16. History of malabsorption syndrome or other condition that would
interfere with enteral absorption.
17. Any of the following within 6 months of randomization:
myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI-CTCAE v.5.0 grade ≥2, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or
symptomatic pulmonary embolism.
18. Uncontrolled electrolyte disorders of NCI-CTCAE v.5.0 grade ≥2. 19. Known hypersensitivity to palbociclib or any of its excipients. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| From a clinical point of view, the primary endpoint for this study is the PFS assessed by RECIST criteria v.1.1, of continuation of palbociclib treatment combined with second-line endocrine therapy (letrozole or fulvestrant) versus endocrine therapy in pre- and post- menopausal women with HR-positive/HER2-negative ABC. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From randomization until objective tumor progression or death. |
|
| E.5.2 | Secondary end point(s) |
-Patient safety and adverse events (AEs) will be evaluated using
the NCI-CTCAE v.5.0. Grade 3 and 4 AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of the different treatment arms.
-ORR, CBR, DoR, TTR, TTP, OS of continuation of palbociclib treatment combined with second-line endocrine therapy
(letrozole or fulvestrant) versus endocrine therapy.
-Overall change from baseline in patient reported global QOL,
general health status, functioning and symptoms.
-Time to deterioration in global quality of life.
-Time to deterioration in pain.
-Time to first chemotherapy.
-Tumor biopsies taken at baseline will be processed to perform correlation between intrinsic molecular subtypes, based on the 50-gene intrinsic subtype classifier PAM50, and the efficacy endpoints (PFS, ORR, CBR, DoR, TTR, TTP, OS, QOL).
-Potential molecular markers of sensitivity/resistance and molecular alterations involved in Rb-cell-cycle dependent and endocrine-related pathways as a result of CDK4/6 inhibition in patients treated with palbociclib in combination with second-line endocrine therapy. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From randomization until objective tumor progression or death. |
|
| 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 | 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 | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| 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 |
| France |
| Germany |
| Italy |
| Slovenia |
| Spain |
| United Kingdom |
|
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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