| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| To determine whether the addition of palbociclib to adjuvant endocrine therapy will improve outcomes over endocrine therapy alone for HR+/HER2- early breast cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| To determine whether the addition of palbociclib to adjuvant endocrine therapy will improve outcomes over endocrine therapy alone for HR+/HER2- 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 | 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 | 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 invasive disease-free survival (iDFS) for the combination of at least 5 years endocrine therapy and 2-year palbociclib treatment versus at least 5 years endocrine therapy alone in patients with histologically confirmed HR+/HER2- invasive early breast cancer (EBC). |
|
| E.2.2 | Secondary objectives of the trial |
To compare the following endpoints: iDFS excluding second primary invasive cancers of non-breast origin, distant recurrence-free survival (DRFS), locoregional recurrences-free survival (LRRFS), and overall survival (OS).
To compare the safety of 2 years of palbociclib with adjuvant endocrine therapy versus adjuvant endocrine therapy alone.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
(1) Signed informed consent obtained prior to any study specific assessments and procedures.
(2) Age ≥18 years (or per national guidelines).
(3) Premenopausal and postmenopausal women or men with Stage II (Stage IIA limited to a max. of 1000 patients) or Stage III early invasive breast cancer per AJCC Breast Cancer Staging version 7 /UICC . Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice.
(4) Patients with multicentric and/or multifocal and/or bilateral early invasive breast cancer whose histopathologically examined tumors all meet pathologic criteria for ER+ and/or PR+ and HER2-.
(5) Patients must have histologically confirmed hormone receptor positive (ER+ and/or PR+), HER2-, early invasive breast cancer. ER, PR and HER2 measurements should be performed acc. to institutional guidelines, in a CLIA-approved setting in the US or certified laboratories for Non-US regions. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP guidelines. Patients with equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines are eligible, as long as they have not received and are not scheduled to receive anti-HER2 treatment. Testing may occur on diagnostic core or surgical tumor tissue.
(6) Patients must have undergone breast surgery for the current malignancy.
(7) A formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be transmitted to a central sample repository and confirmation of receipt must be available prior to randomization.
(8) ECOG performance status 0-1.
(9) Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
(10) Serum or urine pregnancy test must be negative within 7 days of randomization in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential and male patients randomized into treatment Arm A or B must use adequate contraception for the duration of protocol treatment and for 6 months after the last treatment with palbociclib if they are in arm A. In addition, patients receiving standard adjuvant endocrine therapy (Arm A and Arm B) should use adequate contraception in accordance with the specific medication requirements (e.g. SmPC).
Prior Treatment Specifics
(11) Patients may or may not have received neo/adjuvant therapy, but must be after last dose of chemotherapy and/or biologic therapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
(12) Patients may or may not have received breast/axilla/post-mastectomy chest wall radiotherapy, but must be after last dose of radiotherapy and must have sufficient resolution of side effects per physician assessment at the time of randomization.
(13) Patients must have sufficient resolution of any surgical side effects from the last surgery per physician assessment with no active wound healing complications at the time of randomization.
(14) Patients must either be initiating or have already started adjuvant hormonal treatment. Patients may already have initiated endocrine therapy at the time of randomization, but randomization must take place within 12 months of date of histological diagnosis and within 6 months of initiating standard adjuvant endocrine therapy. Patients who received neoadjuvant endocrine therapy are eligible as long as they are randomized within 12 months of initial histological diagnosis and after completing no more than 6 months of adjuvant endocrine therapy. Patients may be receiving either tamoxifen or aromatase inhibitor (AI: letrozole, anastrozole, or exemestane). For premenopausal patients and men, concurrent LHRH agonist use is allowable and may also be ongoing at the time of randomization. If a LHRH agonist was used for ovarian protection during neo/adjuvant chemotherapy it is allowable and shall not be taken into account for calculations regarding the 6 months standard adjuvant endocrine therapy.
Baseline Body Function Specifics
(15) Absolute neutrophil count ≥ 1,500/mm3
(16) Platelets ≥ 100,000/ mm3
(17) Hemoglobin ≥ 10g/dL
(18) Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert’s Syndrome.
(19) Aspartate amino transferase (AST or SGOT) and alanine amino transferase (ALT or SGPT) ≤ 1.5 × institutional ULN.
(20) Serum creatinine below the upper limit of the institutional normal range (ULN) or creatinine clearance (or glomerular filtration rate [GFR]) ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN. |
|
| E.4 | Principal exclusion criteria |
(1) Concurrent therapy with other Investigational Products.
(2) Prior therapy with any CDK inhibitor.
(3) Patients with Stage I or IV breast cancer are not eligible. Baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice.
(4) History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
(5) Patients receiving any medications or substances that are potent inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization.
(6) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
(7) Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Breastfeeding must be discontinued prior to study entry.
(8) Patients with a history of any malignancy are ineligible except for the following circumstances:
• Patients with a malignancy history other than invasive breast cancer are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy.
• Patients with the following cancers are eligible, even if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and non-metastatic non-melanomatous skin cancer.
(9) Patients are not eligible if they have previously received endocrine therapy within 5 years prior to diagnosis of the current malignancy. This includes use for prophylactic reasons, including treatment of osteoporosis or cancer prevention with tamoxifen, raloxifene or AI. Patients may concurrently receive bisphosphonates or rank ligand inhibitors while on this study if necessary for treatment or prevention of osteopenia or osteoporosis.
(10) Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
(11) Patients with clinically significant history of chronic liver disease, including chronic/active viral or
other known hepatitis, current alcohol abuse, or cirrhosis, etc.
(12) Patients receiving concurrent exogenous hormone therapy (hormone replacement therapy, oral or any other hormonal contraceptives such as hormonal contraceptive coil, etc.) are not eligible but topical vaginal estrogen therapy is allowable.
(13) QTcF > 480 msec
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Invasive disease-free survival (iDFS) defined acc. to STEEP criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| First interim analysis will take place after first 157 iDFS events have occured (33% of total number of iDFS events; estimated <3 years after FPI) and the second interim analysis after accrual is completed and 313 iDFS events have occured (67% of total iDFS events; estimated <4 years after FPI). The final analysis of iDFS will occur when 469 iDFS events (100%) are observed. |
|
| E.5.2 | Secondary end point(s) |
(1) Invasive disease-free survival (iDFS) excl. second primary invasive cancers of non-breast origin as an event.
(2) Overall Survival (OS)
(3) Locoregional recurrences-free survival (LRRFS) defined as the composite of local/regional ipsilateral recurrence, contralateral invasive breast cancer or death from any cause
(4) Distant recurrence free survival (DRFS) is defined acc. to STEEP criteria as the composite of distant recurrence or death from any cause.
(5) Adverse Events
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| For the first secondary endpoint, first interim analysis will take place after first 157 iDFS events have occured (33% of total number of iDFS events; estimated <3 years after FPI) and the second interim analysis after accrual is completed and 313 iDFS events have occured (67% of total iDFS events; estimated <4 years after FPI). The final analysis of iDFS will occur when 469 iDFS events (100%) are observed. All other secondary endpoints will be analyzed after the occurence of 469 iDFS events. |
|
| 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 | 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 | No |
| 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) | No |
| 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 | 35 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 171 |
| 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 |
| China |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Singapore |
| Taiwan |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Switzerland |
| 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
|
| End of study is the date when the last patient has completed their end of study visit, all data have been collected, and all queries have been resolved. |
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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 | 15 |
| 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 | 15 |
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