| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Localized ER+ breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Localized breast cancer that is also found to be sensitive to anti-hormonal therapy. Before inclusion in the study; tumor should have been recently and completely removed surgically. |
|
| 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 | 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 | 21.1 |
| E.1.2 | Level | PT |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10006290 |
| E.1.2 | Term | Breast and nipple neoplasms malignant |
| 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 | HLGT |
| E.1.2 | Classification code | 10006291 |
| E.1.2 | Term | Breast neoplasms malignant and unspecified (incl nipple) |
| 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 | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| 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 |
| The primary objective of this trial is to assess the efficacy of the combination of at least 5 year endocrine therapy and 2 year-palbociclib as adjuvant systemic treatment instead of adjuvant chemotherapy followed by endocrine therapy in older patients with stage II-III ER+/HER2- early breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy with respect to different time-to-event endpoints (distant recurrence-free interval (DRFI), breast cancer specific survival (BCSS), OS) at 3, 6 and 10 years in both arms
- To evaluate toxicity in both arms
- To evaluate the treatment discontinuation and dose reduction rates in both arms
- To assess the reasons for treatment discontinuation
- To evaluate completion of oral therapy in the experimental arm
- To assess the evolution of Health-Related Quality of Life (HRQoL) in both arms
- To assess the evolution, prognostic and predictive effects of geriatric assessment in both arms
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Women or men with stage II or stage III, early invasive breast cancer
according to the UICC 8th edition for TNM classification
- Histologically confirmed ER+ (at least 10 % of cells staining positive
for ER), HER-2 negative, early invasive breast cancer based on results of
local pathology. Testing may be performed on diagnostic core biopsy or
resection specimen.
- In patients with multicentric, multifocal and/or bilateral breast cancer,
all histopathologically examined invasive tumors must meet pathologic
criteria regarding ER and HER2-status described above.
- Adjuvant chemotherapy indicated and feasible according to treating
physician and patient, based on standard clinicopathological parameters
(tumor size, lymph node involvement, general health status,
proliferation marker, patient wish) and gene expression profile if
available.
- Adjuvant chemotherapy with both anthracycline and taxanes (in
combination or in sequence) considered not indicated or not feasible
according to treating physician.
- Age ≥70 years
- WHO Performance status 0-2
- Completed G8 geriatric assessment within 3 weeks of randomization.
- Participation in translational research is mandatory and therefore
patient must consent for it. Patient should allow sequential sampling of
blood during the course of the trial
- Patient must have undergone breast +/- axillary surgery with curative
intent for the current malignancy ≤12 weeks before randomization. The
final primary tumor surgical specimen must have R0 margins free from
tumor.
- 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.
- Incentive to undergo adjuvant radiation therapy when indicated per
local institutional guidelines.
Note: For patients in the palbociclib arm, radiation therapy when
indicated has to start ≤13 weeks after last surgery. The endocrine
therapy can be initiated during or after the radiation therapy but not
later than 4 weeks after the last radiotherapy. Palbociclib has to start ≤4
weeks after the last radiotherapy. When radiation therapy is not
indicated, endocrine therapy and palbociclib have to be initiated ≤13
weeks after last surgery. Note: For patients in the chemotherapy arm,
chemotherapy has to be the first adjuvant treatment and has to start ≤
13 weeks after the last surgery. When radiation therapy is indicated, this
treatment has to start ≤9 weeks after the last chemotherapy
administration. Adjuvant endocrine therapy can be initiated during or
after the radiation therapy but not later than 4 weeks after the last
radiotherapy. When radiation therapy is not indicated, endocrine therapy
has to be initiated ≤6 weeks after last chemotherapy administration.
- Adequate baseline organ function, evidenced by the following
laboratory results within 3 weeks of randomization:
- Hemoglobin ≥ 9 g/dL
- Absolute neutrophil count (ANC) ≥ 1500/mm3
- Platelet count ≥ 100,000/mm3
- Total bilirubin ≤ 1.5 upper limit of normal (ULN), or total bilirubin ≤ 3.0
×ULN in patients with documented Gilbert's Syndrome.
- Glomerular Filtration Rate (GFR) ≥ 30 ml/min according to MDRD
formula or CKD-EPI formula or Cockcroft and Gault formula
- SGOT (AST), SGPT (ALT) and alkaline phosphatase ≤ 2.5 × ULN
- Patients must be able and willing to swallow and retain oral medication
without a condition that would interfere with enteric absorption.
For men participating in the trial:
• As fertility may be affected permanently with protocol treatment, we
advise offering to patient sperm preservation prior to treatment.
• With female partners of childbearing potential, men must remain
abstinent or use a condom plus an additional contraceptive** method
that together result in a failure rate of <1% per year during the
treatment period and for 6 months after the last dose of chemotherapies
or 3 months and half (14 weeks) after the last dose of palbociclib. Men
must refrain from donating sperm during the same period.
• With pregnant female partners, men must remain abstinent or use a
condom during the treatment period and for 6 months after the last dose
of chemotherapies or 3 months and half (14 weeks) after last dose of
palbociclib to avoid exposing the embryo.
** For female partner, a highly effective method of birth control
includes:
• Combined (estrogen and progestogen containing) hormonal
contraception associated with inhibition of ovulation (oral, intravaginal,
transdermal)
• Progestogen-only hormonal contraception associated with inhibition of
ovulation (oral, injectable, implantable)
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence
- Signed, written informed consent. |
|
| E.4 | Principal exclusion criteria |
- Evidence of macroscopic distant metastases, investigated according to
local institutional guidelines.
- Previous history of invasive breast cancer
- Systemic anticancer therapy prior to the breast cancer surgery
- Prior therapy with any CDK4/6 inhibitor
- Concurrent investigational agent within 28 days of randomization or
five elimination half-lives, whichever is longer
- Concomitant anticancer treatment with the exception of bone
antiresorptive agents or LHRH agonists in male patients treated with an
aromatase-inhibitor
- History of allergic reactions attributed to compounds of chemical or
biological composition similar to palbociclib or to chemotherapy
components
- Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency, or glucose-galactose malabsorption
- Medications or substances that are potent inhibitors or inducers of
CYP3A isoenzymes within 7 days of randomization
- History of extensive disseminated/bilateral or known presence of
interstitial fibrosis or interstitial lung disease, including a history of
pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia,
interstitial lung disease, obliterative bronchiolitis, and pulmonary
fibrosis, but not history of prior radiation pneumonitis.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (including known HIV, active hepatitis B and/or
hepatitis C infection), symptomatic congestive heart failure, unstable
angina pectoris, uncontrolled cardiac arrhythmia, or uncontrolled
diabetes.
Note: For patients for whom doxorubicin or epirubicin is planned, an
adequate baseline cardiac function (left ventricular ejection fraction ≥
50%) should have been proven no more than 1 year before treatment
start.
- Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up
schedule; those conditions should be discussed with the patient before
registration in the trial
- Other malignancy within the last 5 years except: adequately treated
non-metastatic non-melanoma skin cancer, curatively treated in situ
cancer of the cervix, ductal carcinoma in situ of the breast.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint in this study is the 3-year distant recurrence-free interval rate in the experimental arm. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 3 years (main analysis), 6 and 10 years (long-term analyses) |
|
| E.5.2 | Secondary end point(s) |
- Distant recurrence-free interval at 3 years in the control arm and at 6 and 10 years in both arms.
- Breast cancer specific survival at 3, 6, and 10 years in both arms.
- Overall survival at 3, 6 and 10 years in both arms.
- Adverse events according to CTCAE v5.0 recorded at every patient visit in both arms.
- Treatment discontinuation and dose reduction rates in both arms.
- Reason for treatment discontinuation.
- HRQoL questionnaires (modified QLQ-C30, ELD-14, and selected items from the BR45 module) at 3 months, 6 months, 1 year, 2 years, and 3 years in both arms.
- Geriatric assessment tools (G8, iADL, ADL, Gait speed, CCI, social situation) at 3 months, 6 months, 1 year, 2 years, and 3 years in both arms.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 3 years (main analysis), 6 and 10 years (long-term analyses) |
|
| 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 | No |
| 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 | No |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 79 |
| 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 |
| Belgium |
| France |
| Germany |
| Italy |
| Poland |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
| Jordan |
|
| 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 occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment (palbociclib or chemotherapy)
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 11 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| 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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