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 | 18.0 |
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 patients with HER2-negative primary tumors and CTC
♦ 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 |
|
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 |
♦ Prior use of anti-HER2 therapy for any reason or immunotherapy for BC
♦ Prior mediastinal irradiation except internal mammary node irradiation for the present BC
♦ Evidence of unresolved or unstable toxicity from prior surgery, adjuvant chemotherapy or radiotherapy
♦ History of prior invasive breast carcinoma, except for the BC diagnosed and treated before entry. Unifocal or multifocal unilateral (one breast) or unifocal or multifocal synchronous bilateral breast cancer are acceptable if invasive tumor foci are HER2-negative. History of previous ductal carcinoma in situ is allowed.
♦ History of any malignant neoplasms in the past 5 years except for curatively treated basal and squamous cell carcinoma of the skin
♦ Prior autologous or allogeneic stem cell transplantation
♦ 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)
♦ History of other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions
♦ Presence 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.
♦ Concurrent participation in another trial
|
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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.
|
|
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.8.2.4 | 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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 84 |
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
|
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 the primary analysis and for the analysis of the secondary endpoint RFI |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |
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 |