ER-positive Breast Cancer, HER2-negative Breast Cancer, Stage IIB Breast Cancer, Stage III Breast Cancer
Conditions
Brief summary
This is an international, multi-center, randomised, open label, superiority phase III trial of elacestrant vs standard endocrine therapy in patients with ER+/HER2- breast cancer and ctDNA relapse. During the ctDNA screening phase, patients will be tested at different timepoints to detect the presence of ctDNA in their blood. Patients who are found to be ctDNA-positive and have no evidence of distant metastasis, will be randomised 1:1 between standard endocrine treatment (the same they were receiving when tested ctDNA positive) versus elacestrant, provided they meet all eligibility criteria. After completion of the protocol treatment period, treatment will be left at the discretion of the treating physician.
Detailed description
International, multi-center, randomised, open label, superiority phase III trial of elacestrant vs standard endocrine therapy in patients with ER+/HER2- breast cancer and ctDNA relapse. 1. ctDNA screening phase: After verification of the eligibility criteria for screening, patients will enter the ctDNA screening phase of the study in which plasma samples will be collected and tested with ctDNA assay to detect the presence of ctDNA. The test will be performed every 6 months from study entry until the end of accrual (approximately 5.7 years). During the screening phase, patients will be treated with standard adjuvant endocrine therapy \[either tamoxifen or an aromatase inhibitor (exemestane, anastrozole or letrozole)\] and followed-up as per standard of care. The outcome of the serial ctDNA assessments performed during the screening phase will be disclosed to investigators. Patients who are found to be ctDNA-negative at the end of the screening period will not be followed further in this study. Patients who are found to be ctDNA-positive at one of the screening time points will undergo an imaging work-up to assess the presence of distant metastases. Patients for whom the imaging work-up confirms no evidence of distant metastases or locoregional recurrence will be eligible for the randomised phase of the study provided they meet all other eligibility criteria. Patients for whom the imaging work-up shows evidence of distant metastases or locoregional recurrence will be excluded. 2. Randomised trial: Patients will be randomised 1:1 within 4 weeks from the date of ctDNA detection (i.e., the date on which the results of the test are received) between standard endocrine treatment (the same they were receiving when tested ctDNA positive) versus elacestrant. In the absence of a withdrawal criteria, treatment in both arms will be administered for: * For patients on ET between 1 to 5 years (12 to 60 months) at the time of randomisation: 2 to 6 years (allowing for 7 years of ET at the end of the study treatment). * For patients on ET between 5 to 7.5 years (60 to 90 months) at the time of randomisation: 2 years. After completion of the protocol treatment period, treatment will be left at the discretion of the treating physician. Patients in both arms will undergo intensive follow-up with ctDNA tests at week 4 and week 16 after randomisation and every 16 weeks thereafter for a maximum of 3 years (36 months or 156 weeks) to assess ctDNA kinetics. In addition, the occurrence of distant metastases, locoregional recurrences and second cancers will be assessed via yearly mammograms and bone scans and 16-weekly CT scans thorax/abdomen for a maximum of 3 years after randomisation. Afterwards, follow-up will continue as per standard of care. All randomised patients will be followed-up until 3 years after the enrolment of the last patient. End of study: End of study occurs when all the following criteria have been satisfied: All patients have completed their end of study visit. If a patient discontinues the follow-up due to withdrawal of consent, loss to follow-up, or death, the end of study participation is defined as the time point when one of these events occurred The trial is mature for all analyses defined in the protocol and the database has been cleaned and frozen for these analyses.
Interventions
DRUGElacestrant
400mg QD orally on a continuous dosing schedule
DRUGTamoxifen
20 mg QD orally on a continuous dosing schedule
DRUGLetrozole 2.5mg
2.5 mg QD orally on a continuous dosing schedule
DRUGAnastrozole 1mg
1 mg QD orally on a continuous dosing schedule
DRUGExemestane 25 MG
25 mg QD orally on a continuous dosing schedule
Sponsors
Breast International Group
Menarini Group
European Organisation for Research and Treatment of Cancer - EORTC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. ctDNA screening phase: Main inclusion criteria: • Female (both pre- and postmenopausal) or male patients with histologically confirmed ER positive (regardless of PR), HER2 negative breast cancer, according to local pathologist: * ER-positive defined as ≥ 10% of cells staining positive for ER or Allred proportion score ≥3 * HER2-negative defined as a score of 0, 1+ by immunohistochemistry (IHC) or a negative in situ hybridization (ISH) based on single-probe average HER2 copy number, as per American Society of Clinical Oncology guidelines * Intermediate to high risk of recurrence after definitive treatment for early breast cancer, defined as: FOR PATIENTS TREATED WITH PRIMARY SURGERY: * Any patient with ≥ 4 positive axillary lymph nodes (stage pN2-3). * 1-3 positive axillary lymph nodes (stage pN1) and either: * Tumour size ≥ 5 cm or/and * Histologic grade 3 or/and * Ki67≥20% or/and * High genomic risk defined as Oncotype Dx Recurrence Score \>=26, Mammaprint high risk, Prosigna score \>40 or EPclin risk score \>=4.0. * Negative axillary lymph nodes (stage pN0) and tumour size ≥ 5 cm and either * Histologic grade 3 a or/and * Ki67≥20% and/or * High genomic risk defined as Oncotype Dx Recurrence Score \>=26, Mammaprint high risk, Prosigna score \>60 or EPclin risk score \>=4.0. FOR PATIENTS TREATED WITH NEOADJUVANT SYSTEMIC TREATMENT FOLLOWED BY SURGERY: * Patient may have received neoadjuvant endocrine therapy or neoadjuvant chemotherapy provided that: * The initial tumour and/or the tumour after surgery meet the criteria above defined for patients treated with primary surgery or the initial tumour was staged as cT4anyN and * There is no pathological complete response, defined as no invasive disease in the breast and axilla (ypT0/is ypN0). * Age ≥18 years * Patients must have received at least 1 year and up to 7.5 years of ET and planned to continue adjuvant ET during ctDNA screening phase * Previous adjuvant CDK4/6 inhibitor or PARP-inhibitor treatment is allowed provided it is completed * Invasive multicentric / multifocal disease is allowed provided that all the tested foci are ER+ HER2-. A sample from the highest-risk one, according to the investigator decision based on the size and grade, should be sent to Natera to build the patient ctDNA assay. * Available tumour sample from resected or biopsied tissue, with a tumour content of ≥20% (30% preferred) either before or after macro dissection (if performed) and a cell viability of a minimum 100 cells. * Core Needle Biopsies (CNB): recommended minimum of four (4) cores per block * Fine Needle Aspirates (FNA) are not accepted * The following sample types are acceptable: * 6-10 unstained slides (charged and unbaked) of 10μm each (or 12-19 unstained slides at 5 μm each), PLUS one contiguous H&E slide. Minimum total tissue thickness must be 60μm OR * FFPE tissue block with 25mm2 minimum surface area * Written informed consent must be given according to ICH/GCP, and national/local regulations. Main
Exclusion criteria
* Suspected recurrent disease or known conflicts with the inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Distant metastasis free survival (DMFS) | Final DFMS will be 6.25 years after the first patient randomised. | Distant metastasis free survival (DMFS) defined as the time from randomisation until first distant metastatic recurrence or death from any cause, whichever occurs first |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse-free survival (RFS) | Through study completion, up to 11.7 years | Relapse-free survival (RFS) rate according to the STEEP criteria, including locoregional recurrence, distant metastasis, deaths from any cause as events |
| Overall survival rate | Through study completion, up to 11.7 years | Overall survival rate • Safety including but not limited to all adverse events, serious adverse events, laboratory abnormalities graded according to CTCAE version 5.0 |
| Adverse events | as of randomization until 30 days after administration of the last dose of protocol treatment. | Safety including but not limited to all adverse events, serious adverse events, laboratory abnormalities graded according to CTCAE version 5.0 |
| Invasive disease-free survival (iDFS) | Through study completion, up to 11.7 years | According to the STEEP criteria, it's defined as the time between the date of randomisation and the date of the first occurrence of one of the following events: loco-regional disease recurrence, distant metastasis, invasive contralateral breast cancer, invasive non-breast second cancer, or date of death from any cause |
| Health Related Quality of Life EORTC IL146 | weeks 4, 16, 32, 48, 64 and 80 | Health-related quality of life (HRQoL) is a secondary endpoint in this trial. HRQoL assessment aims at 1. establishing the patient-reported tolerability profile in each treatment arm. 2. comparing the patient-reported benefit between the two treatment arms. Assessments will be performed at 21 days before randomisation, 4 weeks, 16 weeks, 32 weeks, 48 weeks, 64 weeks, and 80 weeks after randomisation using the following measures: EORTC IL146. |
| Health Related Quality of Life QLQ-BR42 | weeks 4, 16, 32, 48, 64 and 80 | Health-related quality of life (HRQoL) is a secondary endpoint in this trial. HRQoL assessment aims at 1. establishing the patient-reported tolerability profile in each treatment arm. 2. comparing the patient-reported benefit between the two treatment arms. Assessments will be performed at 21 days before randomisation, 4 weeks, 16 weeks, 32 weeks, 48 weeks, 64 weeks, and 80 weeksafter randomisation using the following measures:QLQ-BR42 |
| Health Related Quality of Life QLQ-C30 | weeks 4, 16, 32, 48, 64 and 80 | European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30). This is a patient-reported questionnaire composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. All of the scales and single-item measures range in score from 0 to 100.A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. Assessments will be performed at 21 days before randomisation, 4 weeks, 16 weeks, 32 weeks, 48 weeks, 64 weeks, and 80 weeks after randomisation using the following measures: QLQ-C30 |
Countries
Belgium, Cyprus, France, Germany, Greece, Ireland, Italy, Netherlands, Spain, Sweden, Switzerland
Contacts
Primary ContactEORTC HQ
Outcome results
None listed