| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 17.1 |
| 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 |
The objectives of this study are to determine:
1.Is there a role for CEP17 and TOP2A testing in selecting anthracycline or taxane chemotherapy as neo-adjuvant chemotherapy for early breast cancer?
2.Is SLNB post neo-adjuvant chemotherapy in patients with biopsy proven ipsilateral axillary lymph node metastasis at diagnosis sufficiently sensitive to replace routine axillary node clearance?
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| E.2.2 | Secondary objectives of the trial |
The primary translational science objective of the ROSCO trial is to validate the use of a predictive biomarker of anthracycline sensitivity for clinical use in neo-adjuvant breast cancer. A secondary exploratory objective will be to use a tissue, Deoxyribonucleic Acid (DNA), and serum/plasma sample repository from consented patients to extend current translational research into candidate biomarkers of chemotherapy response, predictive markers of response to chemotherapy without invasive testing, and pharmacogenomics to investigate potential markers of toxicity.
The patient experience during and after chemotherapy is also important to describe in ROSCO. A standard Quality of Life (QoL) evaluation will be performed. Patients will be requested to complete a QoL Booklet at specific time points during and after treatment.
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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 |
ROSCO Translational Science
Quality of Life and Health Economic Sub-study
These sub-studies are integral to the main trial protocol and thus has the same version number and date.
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| E.3 | Principal inclusion criteria |
ROSCO Main Trial
• Patient with histological diagnosis of invasive breast cancer
• Suitable for neo-adjuvant chemotherapy in opinion of investigator
• Unifocal tumour:
- Radiological size greater than or equal to (≥) 20 mm by ultrasound (or in some cases Magnetic Resonance Imaging (MRI) is allowed)
- T4 tumour of any size with direct extension to (a) chest wall or (b) skin or both
- Inflammatory carcinoma with tumour of any size
OR
Multifocal tumour:
- The sum of each tumour’s maximum diameter must be ≥20 mm (total sum of multifocal deposits ≥20 mm by ultrasound)
OR
Other locally advanced disease
- Biopsy confirmed axillary lymph node involvement or large or fixed axillary lymph nodes (radiological diameter ≥20 mm or clinical N2), or ipsilateral supraclavicular nodes and primary breast tumour of any diameter
- Involvement of large or fixed axillary lymph nodes (radiological diameter ≥20 mm or clinical N2), or ipsilateral supraclavicular nodes without a primary breast tumour identified: in this case the presence of breast cancer in a lymph node must be histopathologically confirmed by lymph node biopsy (trucut or whole lymph node)
• Patients with bilateral disease are eligible to enter the trial, if one of the criteria above is met for disease in at least one breast
• Any HER2 status
• Patient fit to receive the trial chemotherapy regimen in the opinion of the responsible clinician. The following recommendations must be taken into account when making this assessment:
- Patients with HER2 positive disease must not have clinically significant cardiac abnormalities. Cardiac function should be assessed by physical examination and baseline measurement MUST be made of Left Ventricular Ejection Fraction (LVEF) by Multi Gated Acquisition (MUGA) scan or echocardiogram (ECHO). LVEF must be within the normal range as defined locally by the treating hospital
- Patients must have adequate bone marrow, hepatic, renal and haematological function
• Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1
• Women of child-bearing potential, or men in a relationship with a woman of child-bearing age, prepared to adopt adequate contraceptive measures if sexually active
• 18 years or older
• Male or female
• Written informed consent for the trial
• Availability of embedded paraffin tumour blocks from pre-chemotherapy biopsy is required
• Willing and able to comply with scheduled visits, treatment plan and other study procedures
Sentinel Lymph Node Biopsy Study (in addition to above)
• Biopsy/fine needle aspiration proven involved ipsilateral axillary lymph nodes at diagnosis
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| E.4 | Principal exclusion criteria |
ROSCO Main Trial
• Tumours of low or intermediate grade (Grade 1 or 2) which are also Oestrogen Receptor (ER) rich and Progesterone Receptor (PgR) rich or PgR unknown, whatever the size or nodal status
• Previous invasive breast cancer
• Unequivocal evidence of metastatic disease
• Previous diagnosis of other malignancy unless:
- Disease-free for 5 years; or
- Previous basal cell carcinoma, cervical carcinoma in situ, superficial bladder tumour; or
- Contralateral or ipsilateral DCIS of the breast treated by surgery alone
• Previous chemotherapy
• Prior extensive radiotherapy (as judged by the investigator) to bone marrow
• Previous neo-adjuvant endocrine therapy (unless less than 6 weeks duration)
• Concomitant hormonal therapies/chemotherapy or any other medical treatment in relation to treating the breast cancer
• In HER2 positive patients risk factors precluding co-administration of trastuzumab and FEC75
- Previous myocardial infarction during the 6 months prior to recruitment
- LVEF below institutional lower limit of normal and no echocardiographic evidence of heamodynamically
- Significant valvular heart disease or ventricular contractility
• Prior diagnosis of cardiac failure
• Uncontrolled hypertension, coronary heart disease other significant cardiac abnormality
• Bleeding diathesis
• Presence of active uncontrolled infection
• Any evidence of other disease which in the opinion of the investigator places the patient at high risk of treatment related complication
• Pregnant (female patients of child bearing potential should have a urine or blood Human Chorionic Gonadotropin test performed to rule out pregnancy prior to trial entry)
• Lactating females
• Any concomitant medical or psychiatric problems which in the opinion of the investigator would prevent completion of treatment or follow-up
Sentinel Lymph Node Biopsy Study (in addition to above)
• Negative nodes at diagnosis
• SLNB at diagnosis
• Allergy to patent blue dye
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete pathological response (pCR) rate: pCR will be determined at surgery in patients following treatment with neo-adjuvant chemotherapy and will be defined as no residual invasive carcinoma within the breast (Ductal Carcinoma In Situ (DCIS) permitted) and no evidence of metastatic disease within the lymph nodes. The number of patients achieving pCR as a proportion of those randomised will be presented. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Following surgical resection |
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| E.5.2 | Secondary end point(s) |
1. pCR rate in breast alone: defined by the number of patients who have no residual invasive carcinoma within the breast (DCIS permitted) as a proportion of those randomised
2. Clinical response in breast alone: defined as the number of patients with complete response (CR) or partial response (PR), measured by callipers at baseline and on completion of treatment, as a proportion of the number of patients randomised. Response will be assessed using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
3. Radiological response in breast alone: defined as the number of patients with CR or PR, measured by ultrasound (or MRI if used at baseline when ultrasound unavailable) at baseline and on completion of treatment, as a proportion of the number of patients randomised. Response will be assessed using RECIST version 1.1.
4. Rates of breast conservation: defined as the number of patients treated with breast conservation as a proportion of the total number of patients receiving surgery. The number of patients who are assessed as requiring mastectomy prior to chemotherapy and subsequently are down staged to permit a breast conserving final surgical procedure as a proportion of the total number of patients assessed as requiring mastectomy prior to chemotherapy
5. Tolerability and toxicity of treatment: Tolerability will be measured in terms of the mean number of cycles received and the proportion of patients receiving all 4 cycles. Toxicity will be measured in terms of the occurrence, severity, type and causality of Adverse Events during the treatment period
6. Sensitivity of SLNB following neo-adjuvant chemotherapy in patients who were node positive by biopsy at outset: defined as the sensitivity rate of SLNB, that is the number of patients correctly identified by SLNB as having lymph node involvement as a proportion of all patients with confirmed lymph node involvement following axillary clearance at surgery
7. Correlation between SLNB post-surgery and residual tumour burden in axilla: The correlation between false negative SLNB post-surgery and residual tumour burden in axilla as measured by isolated tumour cells, micrometastases, macrometastases
8. Time until loco-regional recurrence: defined in whole days, as the time from randomisation until loco-regional recurrence (ipsilateral recurrence within the breast, axillary and supraclavicular fossa nodes). Patients who withdraw or who are lost to follow-up will be censored at the date last known to be alive and relapse free. Patients not having an event will be censored at the date last seen alive and relapse free or date of death in death occurred without documenting a relapse
9. Disease Free Survival (DFS): defined in whole days, as the time from randomisation until disease recurrence or death from any cause, whichever is first. Patients who withdraw or who are lost to follow-up will be censored at the date last known to be alive and disease free. Patients not having an event will be censored at the date last seen alive and relapse free
10. Distant Disease Free Survival: defined in whole days, as the time from randomisation until first documented distant disease or death from any cause, whichever is first. Patients who withdraw or who are lost to follow-up will be censored at the date last known to be alive and distant disease free. Patients not having an event will be censored at the date last seen alive and free of distant disease
11. Overall Survival: defined in whole days as the time from randomisation until death from any cause. Patients who withdraw or who are lost to follow-up will be censored at the date last known to be alive. Patients remaining alive throughout the duration of the study will have their survival time censored on the date last seen alive
12. Quality of Life (QoL): will be determined using the Functional Assessment of Cancer Therapy Breast Cancer (FACT B) and EuroQoL EQ-5D QoL questionnaires
13. Health Economics: cost per quality of life adjusted year (QALY) will be calculated using the EQ-5D questionnaire and key resource use data from Case Report Forms (CRFs)
14. Utility of alternative molecular predictors of differential response to treatment with different drugs regimens will be explored
15. Pharmacogenetic analysis to identify differences in toxicity and efficacy in individuals with specific gene polymorphisms
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Following surgical resection
2. On completion of protocol treatment
3. On completion of protocol treatment
4. Following surgical resection
5. Measured on completion of each cycle of chemotherapy
6. Following surgical resection
7. Following surgical resection
8. Measured continually
9. Measured continually
10. Measured continually
11. Measured continually
12. Will be measured at baseline, on completion of 2 and 4 cycles of neo-adjuvant chemotherapy, 6 weeks after completion of surgery and 1 and 2 years post-randomisatiom
13. Measured on completion of each cycle of chemotherapy
14 - 15. Analyses will be performed retrospectively
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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 | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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) | 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 | 100 |
| E.8.5 | The trial involves multiple Member States | No |
| 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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| The end of trial will be 6 months after the last patients’ last visit. This will allow sufficient time for the completion of protocol procedures, data collection and data input. |
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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 | 10 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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