| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| About one-third of patient with hormone-receptor positive, HER2 negative breast cancer and residual disease after standard of care - including adequate surgery - have a substantial risk of relapse despite the use of adjuvant endocrine therapy. |
|
| E.1.1.1 | Medical condition in easily understood language |
| To determine if the addition of palbociclib to standard care is beneficial to patients with residual disease after having received chemotherapy before surgery as treatment for early 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 | PT |
| E.1.2 | Classification code | 10057654 |
| E.1.2 | Term | Breast cancer female |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006200 |
| E.1.2 | Term | Breast cancer stage II |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006202 |
| E.1.2 | Term | Breast cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006201 |
| E.1.2 | Term | Breast cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071113 |
| E.1.2 | Term | Node-positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10025025 |
| E.1.2 | Term | Lumpectomy (breast cancer) |
| E.1.2 | System Organ Class | 100000004865 |
|
| 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 | 10073289 |
| E.1.2 | Term | Premenopausal breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10070575 |
| E.1.2 | Term | Estrogen receptor positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10072740 |
| E.1.2 | Term | Locally advanced breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10070577 |
| E.1.2 | Term | Oestrogen receptor positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 invasive disease free survival (iDFS) for palbociclib vs. placebo in patients with residual invasive breast cancer and high CPS-EG score after neoadjuvant chemotherapy receiving standard adjuvant endocrine therapy for hormone-receptor positive, HER2 normal primary breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
To compare between the 2 treatment arms:
• iDFS excluding second non-breast cancers,
• overall survival (OS),
• distant disease free survival (DDFS),
• locoregional recurrences-free (LRRFS) survival,
• iDFS per treatment group in patients with luminal-B tumors (as determined by e.g. PAM50 or any other commercially available test at the time of analysis),
• compliance and safety according to NCI-CTCAE version 4.0,
• patients reported outcomes,
• health economic outcomes,
• to explore drug-drug interactions (DDI) potential for palbociclib - endocrine combination therapy in a subset of this patient population,
• to explore correlations between exposure and efficacy and/or safety findings.
Other objectives:
Scores and markers for their prognostic value in this specific trial setting and their predictive information on the efficacy and/or safety of palbociclib. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements.
2. Willingness and ability to provide archived formalin-fixed paraffin-embedded tissue block or a partial block from surgery after neoadjuvant chemotherapy and from core-biopsy before start of neoadjuvant chemotherapy, which will be used for centralised retrospective confirmation of hormone- and HER2-status and to evaluate correlation between genes, proteins, and mRNAs relevant to the endocrine and cell cycle pathways and sensitivity/resistance to the investigational agents. In case of bilateral breast cancer, tumor tissue of both sides needs to be assessable.
3. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the breast.
4. Residual invasive disease post-neoadjuvant either in the breast or as residual nodal invasion.
5. Centrally confirmed hormone-receptor positive (≥ 1% ER and/or PR positive stained cells) and HER2 normal status (IHC score 0-1 or FISH negative: in-situ hybridization [ISH] ratio < 2.0) assessed preferably on tissue from post-neoadjuvant residual invasive disease or core biopsy of the breast, or if no other tissue is available the residual tumor of the lymph node can be assessed. In case of bilateral breast cancer hormone-receptor positivity and HER2 normal status has to be centrally confirmed for both sides.
6. Centrally assessed Ki-67, pRB, and cyclin D1 status assessed preferably on post-neoadjuvant residual invasive disease of the breast, or if not possible, of residual nodal invasion or core biopsy. In case of bilateral breast cancer, tumor tissue of both sides needs to be assessable.
7. Patients must have received neoadjuvant chemotherapy of at least 6 cycles at a minimum duration of 16 weeks. This period must include 6 weeks of a taxane-containing therapy (exception: Patients with progressive disease that occurred after at least 6 weeks of taxane-containing neoadjuvant treatment. A total treatment period of less than 16 weeks is also eligible).
8. Adequate surgical treatment including resection of all clinically evident disease and ipsilateral axillary lymph node dissection. Histologically complete resection (R0) of the invasive and ductal in-situ tumor is required in case of breast conserving surgery as the final treatment. No evidence of gross residual disease (R2) is required after total mastectomy (R1 resection is acceptable). Axillary dissection is not required in patients with a negative sentinel-node biopsy before (pN0, pN+[mic]) or after (ypN0, ypN+[mic]) neoadjuvant chemotherapy.
9. Less than 16 weeks interval since the date of final surgery or less than 10 weeks from completing radiotherapy (whichever occurs last) at date of randomisation.
10. Completion of adjuvant radiotherapy according to standard guidelines (e.g. AGO Mamma, NCCN) is strongly recommended. If radiotherapy is not performed the reason for this needs to be documented in the eCRF.
11. No clinical evidence for locoregional or distant relapse during or after preoperative chemotherapy. Local progression during chemotherapy is not an exclusion criterion.
12. A clinical-pathologic stage - estrogen/grade (CPS-EG) score of ≥ 3 or score 2 if nodal status at surgery is ypN+, calculated using local estrogen receptor status and grade assessed on either core biopsies taken before start of neoadjuvant treatment or surgical specimen.
13. Age at diagnosis at least 18 years.
14. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
15. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
16. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast cancer.
17. The patient must be accessible for scheduled visits, treatment and follow-up. Patients registered on this trial must be treated at the participating center which could be the Principal´s or a Co-investigator's site. |
|
| E.4 | Principal exclusion criteria |
1. Known severe hypersensitivity reactions to compounds similar to palbociclib or palbociclib/placebo excipients or to endocrine treatments.
2. Inadequate organ function immediate prior to randomisation including: Hemoglobin < 10g/dL (100g/L); ANC < 2,000/mm³ (< 2.0 x 109/L); Platelets < 100,000/mm³ (< 100 x 109/L); AST and/or ALT > 1.5x upper normal limits (ULN); Alkaline phosphatase > 2.5x ULN; Total serum bilirubin > 1.25x ULN; Serum creatinine > 1.25x ULN or estimated creatinine clearance < 60mL/min as calculated using the method standard for the institution; severe and relevant co-morbidity that would interact with the participation in the study.
3. Evidence for infection including wound infections, HIV, hepatitis.
4. QTc > 480msec.
5. Uncontrolled electrolyte disorders (e.g., hypocalcemia, hypokalemia, hypomagnesemia).
6. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 grade ≥ 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
7. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.
8. Prior malignancy (including invasive or ductal in-situ breast cancer) within 5 years prior to randomization, except curatively treated basal cell carcinoma of the skin and carcinoma in-situ of the cervix.
9. Current severe acute or uncontrolled chronic systemic disease (e.g., diabetes melittus) 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.
10. Recent (within the past year) or active suicidal behavior.
11. Pregnancy or lactation period. Women of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months.
12. Major surgery within 2 weeks prior to randomization.
13. 10 weeks or more have passed since completion of radiotherapy at day of randomization and 16 weeks interval since the date of final surgery have passed.
14. Prior treatment with any CDK4/6 inhibitor.
15. Patients treated within the last 7 days prior to randomization and/or concurrent use of drugs known to be strong CYP3A4 inhibitors or inducers (see appendix 21.3).
16. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to randomization.
17. Male patients. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is invasive disease-free survival (iDFS). iDFS will be defined according to Hudis et al. (J Clin Oncol 2007) as the time period between randomisation and first event (ipsi- or contralateral invasive in-breast or loco-regional recurrence, distant recurrence, death from breast cancer, death from non-breast cancer cause, death from unknown cause, invasive contralateral breast cancer, second primary invasive cancer [non-breast]). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Final analysis on the primary endpoint and secondary efficacy endpoints (except for OS) will be conducted when 255 events in iDFS have been observed (projected Q-III 2020). Two interim efficacy analyses will be performed in the study. The first interim analysis will take place after the first 85 events (1/3 of the total events) have occurred and the second interim analysis will take place after the first 170 events (2/3 of the total events) have occurred. It was estimated that the first interim analysis will occur approximately 3.7 years from first patient randomised but the accrual duration was estimated to be 3.6 years. It was estimated that the second interim analysis will occur < 5 years from first patient randomised. |
|
| E.5.2 | Secondary end point(s) |
Secondary objectives include comparison between the 2 treatment arms for the secondary endpoints. The secondary endpoints include the following:
• iDFS excluding second non-breast cancers,
• overall survival (OS),
• distant disease-free survival (DDFS),
• locoregional recurrences-free survival (LRRFS),
• iDFS per treatment group in patients with luminal-B tumors as determined by PAM50 or any other commercially available test at the time of analysis,
• compliance and safety according to NCI-CTCAE version 4.0,
• patients reported outcomes,
• health economics,
• drug-drug interaction (DDI potential) for palbociclib - endocrine combination therapy in a subset of this patient population,
• correlations between exposure and efficacy and/or safety findings.
Other endpoints:
Scores and markers for their prognostic value in this specific trial setting and their predictive information on the efficacy and/or safety of palbociclib including:
• residual cancer burden (RCB) 8,
• clinical response to neoadjuvant chemotherapy,
• alterations in genes, proteins, and RNAs relevant to the cell cycle (e.g., CCND1 amplification, CDKN2A deletion), drug targets (e.g., CDK 4/6), and tumor sensitivity and/or resistance (Ki67, phosphorylated Rb [pRb], total RB [tRB], cyclin E, pi3k, p16, and other markers, measured by optimal test available at the time of analysis) in tumor tissues and/or peripheral blood,
• low and high risk groups (defined by EndoPredict risk of relapse [ROR] or other any other available test at the time of analysis),
• low and high risk groups defined by a standardised image analysis system for Ki67,
• circulating tumor DNA (ctDNA). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final analysis on the primary endpoint and secondary efficacy endpoints (except for OS) will be conducted when 255 events in iDFS have been observed (projected Q-III 2020). Two interim efficacy analyses will be performed in the study. The first interim analysis will take place after the first 85 events (1/3 of the total events) have occurred and the second interim analysis will take place after the first 170 events (2/3 of the total events) have occurred. It was estimated that the first interim analysis will occur approximately 3.7 years from first patient randomised but the accrual duration was estimated to be 3.6 years. It was estimated that the second interim analysis will occur < 5 years from first patient randomised.
Final OS will be analysed in Q-III 2023 (projected). |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 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 | 90 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 158 |
| 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 |
| Australia |
| Canada |
| Japan |
| Korea, Republic of |
| United States |
| Austria |
| France |
| Germany |
| Ireland |
| Spain |
| United Kingdom |
|
| 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
|
No interventional procedures after final iDFS (and interim OS) analysis, which will be by Q-III 2020. Overall survival analysis will be in 2023, however no interventional procedures required to collected the data. Survival and relapse follow-up will be post study after 2023.
Participating patients are recommended to be registered in the GBG self-reporting registry (if allowed by national regulations) that will allow further follow up and long-term efficacy evaluations. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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