| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 the combination of palbociclib plus fulvestrant versus palbociclib plus letrozole in terms of progression-free survival (PFS) in patients with hormone-sensitive HER2-negative metastatic or locally advanced breast cancer |
|
| E.2.2 | Secondary objectives of the trial |
To:
- evaluate the safety and tolerability of the combination of palbociclib plus fulvestrant or letrozole
- correlate the safety profile of palbociclib combined with fulvestrant or letrozole with baseline patient characteristics
- compare the time to progression of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole
- compare the clinical response of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole
- compare the duration of response of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole
- compare time to response of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole
- compare the overall survival of the combination of palbociclib plus fulvestrant with palbociclib plus letrozole
- identify potential biomarkers to predict the benefit from palbociclib combined with endocrine therapy
- identify mechanisms of resistance to palbociclib combined with endocrine therapy |
|
| 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 |
Translational sub-studies to evaluate the mechanisms responsible for the acquisition of resistance to endocrine therapy and palbociclib in the clinical setting.
Blood samples at four time points: baseline, 2 weeks and 12 weeks after treatment start and at time of progression would be collected for translational biomarker research. Additionally, patients can optionally consent to provide tissue samples from metastatic tissue at baseline and at time of progression. For non de novo patients, if available, tissue samples from the primary tumor might be also collected.
Further details as per protocol in Appendix IV.
Endpoints
- Presence of different pattern of expression of ESR1 mutations and other CDK4/6 related biomarkers (i.e. Rb, Akt, PIK3, p53 CA cyclin D1, cyclin A2, E2F1...) in liquid biopsies and tissue samples.
- Proteomics analysis to evaluate differential pattern of protein expression from tissue samples.
- Exome and RNA sequencing will be performed in selected samples. |
|
| E.3 | Principal inclusion criteria |
1. Postmenopausal women, as defined by any of the following criteria:
- Age 60 or over
- Age 45 to 59 years and meets ≥ 1 of the following criteria:
- Amenorrhea for ≥ 24 months
- Amenorrhea for < 24 months and follicle-stimulating hormone
within the postmenopausal range (including patients with hysterectomy,
prior hormone replacement therapy, or chemotherapy-induced
amenorrhea)
- Over 18 years of age and bilateral oophorectomy
OR
Premenopausal women provided they are being treated with LHRH
analogues for at least 28 days prior to study entry
2. Eastern Cooperative Oncology Group (ECOG) score lower or equal to 2
3. Histologically confirmed recurrent ER positive (oestrogen and/or progesterone) HER2-negative locally advanced or metastatic BC patients (Breast cancer that have at least 1% of cells staging positive for ER should be considered ER-positive according to NCCN and ASCO guidelines).
4. Patients should not be candidates for a local treatment with a radical intention.
5. No prior hormonal or chemotherapy line in the metastatic setting.
6. Patient must have measurable (according to RECIST 1.1) or non measurable disease with these exceptions
- Patients with only blastic bone lesions are not eligible
- Patients with only pleural, peritoneal or cardiac effusion, or meningeal carcinomatosis are not eligible
7. Life expectancy grater or equal to 12 weeks
8. Adequate organ function:
- Hematological: White blood cell (WBC) count >3.0 x 109/L, absolute neutrophil count (ANC) >1.0 x 109/L, platelet count >75.0 x109/L, and hemoglobin >10.0 g/dL (>6.2 mmol/L)
- Hepatic: bilirubin < 1.5 times the upper limit of normal (x ULN); alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT) <2.5 times ULN. Patients with ALP ≥2.5 times ULN
are eligible if ALP abnormalities are unequivocally related to bone
lesions (radiological assessments performed within 4 weeks prior to
randomization demonstrated bone metastatic disease).
- Renal: serum creatinine < 1.5 x ULN.
9. Exhibit patient compliance and geographic proximity that allow for adequate follow-up.
10. Patient has been informed about the nature of study, and has agreed to participate in the study, and signed the Informed Consent form prior to participation in any study-related activities.
11. No other malignancies within the past five years except adequate treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
12. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCICTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
13. Patient has been informed about the translational sub-study and has
agreed to participate in the collection of blood and tumor tissue samples by
signing the Informed Consent form. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet ANY of the following criteria:
1. ER or HER2 unknown disease
2. HER2 positive disease based on local laboratory results (performed by immunohistochemistry/FISH)
3. Locally advanced breast cancer candidate for a radical treatment.
4. Prior endocrine therapy in the metastatic setting. (Neo)/Adjuvant endocrine therapy is allowed only if the disease-free interval between the end of endocrine therapy and the appearance of metastases in higher than 12 months.
5. Patients with rapidly progressive visceral disease or visceral crisis.
6. Have had a major surgery (defined as requiring general anaesthesia) or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery or patients that may require major surgery during the course of the study.
7. Patients with an active, bleeding diathesis.
8. Have a serious concomitant systemic disorder (e.g. active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator), previous history of bleeding diathesis, or anti-coagulation treatment (The use of low molecular weight heparin is allowed as long as it is used as prophylaxis).
9. Are unable to swallow tablets.
10. History of malabsorption syndrome or other condition that would interfere with enteral absorption.
11. Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day methylprednisolone equivalent (excluding inhaled steroids).
12. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral oedema, 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, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4weeks before randomization
13. Known hypersensitivity to letrozole, fulvestrant or any of their excipients, or to any PD-0332991 excipients.
14. QTc >480 msec on basal assessments, personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
15. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (e.g., hypocalcemia, hypokalemia, hypomagnesemia). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for this study is PFS, which is defined as the time from randomization until objective tumor progression or death, as assessed by the investigator per RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Baseline up to 36 months |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoint-Safety
Patient safety and adverse events will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4. Grade 3 and 4 adverse events and serious adverse events will be assessed to determine the safety and tolerability of the different drug combinations.
Secondary Endpoints-Efficacy
The time to progression (TTP), overall survival (OS), overall response rate (ORR), duration of response (DoR), time to response (TTR) and clinical benefit rate (CBR) will be determined to assess the efficacy of the drug combinations.
TTP is defined as the time from randomization to disease progression, as assessed by the investigator per RECIST v1.1. OS is defined as the time from randomization until death from any cause. The ORR is defined as the proportion of patients with best overall response of confirmed complete response (CR) or partial response (PR) based on local investigator’s assessment according to RECIST criteria guidelines (version 1.1). DoR is defined as the time from documentation of tumor response (either CR or PR) to disease progression. An objective response needs to be confirmed at least 4 weeks after the initial response. TTR is defined as the time from randomization to the first overall tumor response (tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR. The CBR is defined as the percentage of patients who experience a CR, PR or stable disease for at least 24 weeks and assessed by modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From Baseline up to 36 months |
|
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| Russian Federation |
| United Arab Emirates |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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