1. Overall Survival (OS) (Time Frame - 10 years): OS is defined as time from randomization until the death of the patient independent of cause of death. If a patient is not known to have died, OS is censored at the date of last contact.
2. Overall Lead Time Effect (Time Frame - 5 years): This endpoint is a composite measure, defined as the median time from molecular to via Imaging verified Recurrence Lead Time (calculated only for patients in the liquid-biopsy guided Intensive Surveillance arm) + Difference in time to distant recurrence between the two arms (i.e., difference between median time from randomization to distant recurrence for all patients with distant recurrence in the Standard Surveillance arm and median time from randomization to distant recurrence for all patients with distant recurrence in the liquid-biopsy guided Intensive Surveillance arm). The Overall Lead Time Effect will be assessed for all markers in combination.
Secondary outcome:
1. Invasive disease-free survival (IDFS) (Time Frame - 10 years): IDFS is defined as time from randomization until first IDFS event, including any invasive ipsilateral, regional, contralateral, and distant disease recurrence, second primary tumors, or death from any cause as event; non-invasive, in-situ cancer events are excluded. If a patient has not had an event, IDFS is censored at the date of last adequate tumor assessment.
2. Distant disease-free survival (DDFS) (Time Frame - 10 years): DDFS is defined as time from randomization until first DDFS event including metastasis, second primary tumors and death from any cause as event. If a patient has not had an event, DDFS is censored at the date of last adequate tumor assessment.
3. Distant recurrence-free survival (DRFS) (Time Frame - 10 years): DRFS is defined as time from randomization until first DRFS event including metastasis and second primary tumors; death from any cause is not included as event. If a patient has not had an event, DRFS is censored at the date of last adequate tumor assessment.
4. Breast cancer specific survival (BCSS) (Time Frame - 10 years): BCSS is defined as time from randomization until breast cancer associated death of the patient. If a patient is not known to have died, BCSS is censored at the date of last contact. If a patient has died for reasons not associated with breast cancer (by clinical assessment), BCSS is censored at the date of death.
5. Invasive breast cancer free survival (IBCFS) (Time Frame - 10 years): IBCFS is defined as time from randomization until first IBCFS event, including any invasive ipsilateral, regional, contralateral and distant disease recurrence or death from any cause as event; non-invasive, in-situ cancer events are excluded. If a patient has not had an event, IBCFS is censored at the date of last adequate tumor assessment.
6. Overall Survival (OS) after 10 Years (Time Frame - 10 years): OS is defined as time from randomization until the death of the patient independent of cause of death. If a patient is not known to have died, OS is censored at the date of last contact.
7. Molecular to via Imaging verified Recurrence Lead Time in the Interventional arm (Time Frame - 5 years): The Lead Time is defined as time from first molecular relapse to via imaging verified recurrence for all patients in the liquid-biopsy guided Intensive Surveillance arm for whom a via imaging verified recurrence is documented during the 5-year interventional period of the study. If a patient has a via imaging verified recurrence but no documented molecular relapse, the Lead Time for this patient is set to '0'. This secondary endpoint will be assessed for all markers in combination and, where applicable, for each marker separately.
8. Quality of life (QoL) with questionnaires: EORTC QLQ-C30 (Time Frame - 10 years): QoL will be monitored in both groups using a questionnaire which is to be completed every 6 months (EORTC QLQ-C30) in the interventional phase (first five years) and once a year during the five years of follow-up. QoL data will be collected on paper or via a digital health application.
9. Quality of life (QoL) with questionnaires: PA-F12 (Time Frame - 10 years): QoL will be monitored in both groups using a questionnaire which is to be completed every 6 months (PA-F12) in the interventional phase (first five years) and once a year during the five years of follow-up. QoL data will be collected on paper or via a digital health application.
10. Liquid biopsy sensitivity (CA27.29, CEA, CA125, CTC and ctDNA) (Time Frame - 5 years): Sensitivity is defined as the proportion of all patients in the liquid-biopsy guided Intensive Surveillance arm with a recurrence as verified by imaging during the 5-year interventional period of the study that had a positive biomarker result (i.e., molecular relapse) within 36 months before the recurrence as verified by imaging occurred (or within 60 months before the recurrence as verified by imaging occurred if in the first 36 months at least once a year a positive biomarker is measured).
11. Liquid biopsy specificity (CA27.29, CEA, CA125, CTC and ctDNA) (Time Frame - 5 years): Specificity is defined as the proportion of all patients in the liquid-biopsy guided Intensive Surveillance arm with no recurrence as verified by imaging during the 5-year interventional period of the study that had only negative biomarker results (i.e., no indication of molecular relapse) within 36 months before the end of the 5-year interventional period of the study.
12. Liquid Biopsy False-Positive Rate (CA27.29, CEA, CA125, CTC and ctDNA) (Time Frame - 5 years): False-positive rate is defined as the proportion of all patients in the liquid-biopsy guided Intensive Surveillance arm with a positive biomarker result (i.e., molecular relapse) during the 5-year interventional period of the study that had no recurrence as verified by imaging within 36 months after first molecular relapse.
13. Liquid Biopsy False-Negative Rate (CA27.29, CEA, CA125, CTC and ctDNA) (Time Frame - 5 years): False-negative rate is defined as the proportion of all patients in the liquid-biopsy guided Intensive Surveillance arm with only negative biomarker results (i.e., no indication of molecular relapse) that had a recurrence as verified by imaging during the 5-year interventional period of the study.
14. Rate of liquid biopsy positivity (CA27.29, CEA, CA125, CTC and ctDNA) (Time Frame - 5 years): The overall rate of liquid biopsy positivity is defined as the proportion of all patients in the liquid-biopsy guided Intensive Surveillance arm that had at least one positive biomarker result (i.e., molecular relapse) during the 5-year interventional period of the study.
Active Comparator: Intensive Surveillance arm Intensified surveillance. Prospective tumor marker (CA27.29, CA125, CEA), CTC and ctDNA testing of the blood samples. Abnormal findings of either marker (CA27.29 and/or CA125 and/or CEA and/or CTC and/or ctDNA) will be regarded as molecular relapse and trigger diagnostic imaging.
Placebo Comparator: Standard Surveillance arm Surveillance according to national guidelines. Blood samples will not be analyzed immediately and will therefore not trigger imaging. A biobank will be established for retrospective and translational studies. This procedure is necessary to ensure the partially double-blinded study design.
Determination of tumormarkers (CA27.29, CEA, CA125) (Chemiluminescence enzyme immunoassay): CA27.29, CEA and CA125 will be measured with the AIA®-CL1200 by TOSOH BIOSCIENCE (TOSOH CORPORATION, Tokyo, Japan). The CL AIA-PACK assays are two-step chemiluminescence enzyme immunoassay kits. CA27.29/CEA/CA125 present in a test sample is bound to the anti- CA27.29/CEA/CA125 mouse monoclonal antibody immobilized on the magnetic microparticles in one cell (Cell-I). After first incubation, the magnetic microparticles are washed and the enzyme-labeled anti- CA27.29/CEA/CA125 mouse monoclonal antibody that has been reconstituted in another cell (Cell-II) is dispensed into Cell-I. After second incubation, the magnetic microparticles are washed again and are incubated with a chemiluminescent substrate, DIFURAT®. The amount of enzyme-labeled antibodies that bind to the magnetic microparticles is directly proportional to the CA27.29/CEA/CA125 concentration in the test sample. A standard curve is constructed, unknown sample concentrations are calculated by using this curve.
Determination of CTC levels (CellSearch® System): CTCs will be analyzed using the CellSearch® System (Menarini Silicon Biosystems). The CellSearch® system is designed to enumerate CTCs of epithelial origin (CD45-, EpCAM+, cytokeratin 8+ / 18+ and/or 19+). The basic principle is linking a magnetic ferrofluid reagent that contains i. a. antibodies targeting the EpCAM antigen to CTCs. After steps of immunomagnetic capture and enrichment as well as addition of fluorescent reagents (that contain anti-CK-PE, DAPI and anti-CD45-APC), the automatic dispersion to a magnetic cartridge holder takes place. Via strong magnetic field, the magnetically labeled epithelial cells are attracted to the surface of the cartridge where they can be scanned automatically. Images of events where CK-PE and DAPI fluorescence are co-located are presented to the user for final classification. An event is classified as a tumor cell when its morphological features are consistent with that of a tumor cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45-.
Determination of ctDNA levels (RaDaRTM assay): Presence of ctDNA will be analyzed centrally at Inivata Inc. using the RaDaRTM assay. Therefore, primary tumor tissue and peripheral blood specimens will be shipped for centralized analysis to Inivata Inc. RaDaRTM is a tumor-informed approach, beginning with whole exome sequencing of a tumor specimen from a patient's biopsy or surgical resection. SNVs and indels identified from the exome sequencing are prioritized to build a patient specific primer panel of up to 48 tumor-specific somatic variants. Patient specific primers are combined with common SNP primers for NGS for quality control purposes. To detect patient specific ctDNA, NGS testing is performed with the RaDaRTM assay using a multiplex PCR based on the InVision® platform.
Biobanking of blood samples (Translational research): To ensure the possibility of retrospective studies during and after the ongoing study, a biobank will be implemented.
Quelle: ClinicalTrials.gov
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