E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-Negative Early Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
High Risk Early Breast Cancer |
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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 | 18.1 |
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) |
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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 evaluate whether trastuzumab decreases the detection rate of CTC in patients with HER2-negative primary BC by comparing the trastuzumab treated arm to the observation arm. |
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E.2.2 | Secondary objectives of the trial |
♦ To evaluate in a clinical trial setting the feasibility, reliability, within patient reproducibility and variability of the assay for CTC
♦ To compare clinical outcomes (as measured by Recurrence Free Interval (RFI), Invasive Disease Free Survival (IDFS), Disease Free Survival (DFS) and Overall Survival (OS)) between the trastuzumab and observation arms
♦ To assess safety, especially cardiac safety, of trastuzumab in women with HER2-negative primary tumors
♦ To correlate CTC detection rate at baseline and/or week 18 with RFI, IDFS, DFS, OS
♦ To collect biological material in order to perform translational research |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
-Translational Research
-Detection of HER2-positive CTC and response to trastuzumab.
-Primary tumor DNA mutational and mRNA profiles and response to trastuzumab.
-Plasma circulating nucleic acids / proteomics or other biomarkers and response to trastuzumab |
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E.3 | Principal inclusion criteria |
♦ Female gender
♦ Age ≥ 18 years
♦ Written informed consent must be given according to ICH/GCP, and national/local regulations
♦ Availability of peripheral blood draw for CTC blood test
♦ Tumor block or minimum 10 unstained slides of 10 μm of primary tumor must be available prior to registration for centralized HER2 testing
♦ ER status available
♦ Adequately excised non-metastatic and non-relapsed operable primary invasive HER2-negative adeno-carcinoma of the breast that is all of the following*:
♦ Histological Grade > 1 at time of surgery and primary tumor size > 1 cm
♦ the patient should have completed either
♦ adjuvant chemotherapy or
♦ neoadjuvant chemotherapy; in this case residual invasive disease in breast or lymph nodes is required (no complete pathological response)
♦ No further adjuvant chemotherapy treatment planned. Prior chemotherapy with doxorubicin restricted to a total dose of 360 mg/m2 or with epirubicin restricted to a total dose of 720 mg/m2 is allowed
♦ No prior use of anti-HER2 therapy for any reason or other prior use of biological agent or immunotherapy for BC
♦ No prior and or concomitant use of bisphosphonate therapy for any reason
♦ No prior mediastinal irradiation except internal mammary node irradiation for the present BC
♦ Concomitant adjuvant hormonal therapy or radiotherapy (if applicable) is allowed upon physician’s choice
♦ The interval between definitive surgery (neoadjuvant population) or end of adjuvant chemotherapy (adjuvant population) and registration must be at least 3 weeks but no more than 12 weeks
♦ No evidence of unresolved or unstable toxicity from prior surgery, adjuvant chemotherapy or radiotherapy
♦ No history of prior (ipsilateral and/or contralateral) invasive breast carcinoma or ductal carcinoma in situ, except for the BC proposed in this study. Bilateral breast cancer is acceptable if both tumors are HER2- negative and have been diagnosed within 2 years from registration
♦ No history of any malignant neoplasms in the past 5 years except for curatively treated basal and squamous cell carcinoma of the skin
♦ No prior autologous or allogeneic stem cell transplantation
♦ No history of serious cardiac illness or medical conditions, including but not confined to:
♦ History of documented congestive heart failure
♦ High risk uncontrolled arrhythmias
♦ Angina pectoris requiring anti-anginal medication
♦ Clinically significant valvular heart disease
♦ Evidence of transmural infarction on ECG
♦ Poorly controlled hypertension (e.g. systolic > 180 mm Hg or diastolic > 100 mm Hg)
♦ No history of other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions
♦ Absence of 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
♦ No concurrent participation in another trial
* Imaging work up is not mandatory to enter the trial. If there are signs/symptoms suggesting the presence of local relapse or distant metastasis, an appropriate work up should be performed according to the treating physician standard practice. A patient with confirmed local relapse or distant metastasis will no longer be eligible for the trial. |
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E.4 | Principal exclusion criteria |
Please see inclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Difference in detection rate of CTC at week 18 between trastuzumab and observation |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Criteria for CTC detection
The following apply at each time point (baseline and week 18) to decide on positive versus negative CTC Blood Tests, as well as to evaluate detection.
♦ CTC Blood Test: A blood test (2 x 7.5 mL) for the detection of peripheral blood nucleated cell lacking CD45, expressing cytokeratin 8,18,19
♦ Evaluable CTC Blood Test (see chapter 10.3.1
♦ CTC Blood Test positive: ≥ 1 CTC / 15 mL of peripheral blood analyzed
♦ CTC Blood Test negative: No CTC / 15 mL of peripheral blood analyzed
♦ The positive CTC Blood Test will be centrally reviewed based on images. Images will be sent to central lab.
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E.5.2 | Secondary end point(s) |
♦ Recurrence Free Interval (RFI)
♦ Invasive Disease Free Survival (IDFS)
♦ Disease Free Survival (DFS)
♦ Overall Survival (OS)
♦ Safety, especially cardiac safety (as reported in Appendix C NYHA), as graded by NCI-CTCAE v 4.0 grading. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Recurrence Free Interval: calculated as the time between randomization and recurrence of disease, including any invasive ipsilateral breast tumor, local/regional invasive relapse, distant recurrence, and death from breast cancer documented with an imaging study or biopsy (Hudis et al., Ref. 58).
-Invasive Disease Free Survival: calculated as the time between randomization and the occurrence of an invasive disease recurrence or death.
-Disease Free Survival: determined as the time from randomization to either the date of disease progression or the date of death.
-Overall Survival: calculated as the time from randomization to the date of death. |
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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 | No |
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 | 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. At least 2 years after the last patient was randomized ensuring that 50% of patients have achieved 3 years of follow-up (Section 8.1.1).
3. The database has been fully cleaned and frozen for this secondary analysis |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
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 |