| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Breast cancer by postmenopausal women |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057654 |
|
| 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 |
| Primary objective of the study is to demonstrate superiority of letrozole and zoledronic acid over letrozole monotherapy given as 6 months preoperative treatment with respect to tumor response. Response is defined as complete response (CR) or partial response (PR) based on mammography and/or sonography according to modified RECIST criteria at month 6. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare best response based on mammography and/or sonography according to modified RECIST during 6 months of neoadjuvant treatment.
- To compare the number of patients that qualify for breast-conserving surgery rather than mastectomy.
- To compare pathologic complete response (pCR).
- To compare the change in tumor size.
- To compare BC deaths and overall survival.
- To compare the Quality of Life using the FACT-B questionnaire.
- To compare apoptosis (only in patients who take part in the apoptosis substudy)
- To describe the tumor response in subgroups of patients with polymorphism and special gene expression.
- To compare the safety and tolerability. |
|
| 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 |
SENTINA-Subprotocol - Amendment No. 2
Final Version 1.1, 29-Oct-2007
Multicenter study to evaluate sentinel node biopsy within the
context of neoadjuvant (primary systemic) therapy concepts in
breast cancer
Primary study objective
• Number of patients in whom the extent of axillary surgery can be reduced within the
context of neoadjuvant regimens.
Secondary study objectives
• Evaluation of sentinel lymph node (SLN) detection rates after PST
• Evaluation of SLNB "false negative" rates after PST
• Evaluation of the safety of a second SLNB after PST, following an already performed prechemotherapeutic SLNB with no other measures
• Evaluation of detection rates and "false negative" rates after previous SLNB
• Evaluation of axillary recurrence rates
• Significance of intraoperative instantaneous section histology during SLNB after PST |
|
| E.3 | Principal inclusion criteria |
1. Postmenopausal women able to comply with the protocol requirements with primary invasive breast cancer, histologically confirmed by core needle biopsy, whose tumors are estrogen (ER) and / or progesterone (PgR) positive, defined by core biopsy immunohistochemistry with > 10% positive malignant epithelial cells.
2. Clinical Stage T1c (Size >= 1.5 cm), T2, T3, T4a, b, c, N0 or N1, M0
3. Post menopausal status defined by one of the following:
- Age >55 years.
- Age <= 55 but no spontaneous menses for at least 1 year.
- Age <= 55 and spontaneous menses within the past year, but currently amenorrheic (e.g., spontaneous or secondary to hysterectomy), and with postmenopausal gonadotrophin levels (luteinizing hormone and follicle stimulating hormone levels) >40 IU/L or postmenopausal estradiol levels <5 ng/dL or according to the definition of “postmenopausal range” for the laboratory involved.
- Bilateral oophorectomy (prior to the diagnosis of breast cancer).
4. Tumor measurable by mammography, sonography and clinical examination.
5. Adequate renal function (see exclusion criterion 4).
6. Adequate bone marrow function (WBC >=3.5 G/L and platelets >=100.0 G/L, and hemoglobin >11.0 g/dL).
7. Documented evidence of adequate hepatic function (bilirubin <25 mcmol/L, AST (SGOT) <60 U/L).
8. A life expectancy of at least 12 months.
9. ECOG Performance status of 0, 1 or 2.
10. Patients should be assessable for Follow-up.
11. Written informed consent.
|
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with letrozole or bisphosphonates.
2. Patients with unstable angina, or uncontrolled cardiac disease or uncontrolled endocrine disorders.
3. Evidence of inflammatory breast cancer or distant metastasis.
4. Abnormal renal function as evidenced by a calculated creatinine clearance <30 mL/minute.
5. Other concurrent malignant disease with the exception of cone-biopsied in situ carcinoma of the cervix uteri, or adequately treated basal or squamous cell carcinoma of the skin, or other curable cancers e.g. Hodgkin’s disease or non-Hodgkin-lymphoma, provided 5 years have elapsed from completion of therapy, and there has been no recurrence.
6. Prior and concomitant anti-breast-cancer treatments such as chemotherapy, immunotherapy / biological response modifiers (BRM’s), endocrine therapy other than letrozole (including steroids), and radiotherapy. Patients who have received hormone replacement therapy (HRT) will NOT be excluded, provided that HRT is discontinued at least 2 weeks prior to entry into the study.
7. Concomitant treatment with systemic steroids, except for topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops or local injections (e.g. intra-articular).
8. Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.
9. Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants).
10. History of diseases with influence on bone metabolism, such as Paget’s disease, Osteogenesis Imperfecta, and primary or secondary hyperthyroidism within the 12 months prior to study entry.
11. Known hypersensitivity to zoledronic acid, other bisphosphonates or letrozole.
12. Other investigational drugs within the past 30 days and the concomitant use of investigational drugs.
13. History of non-compliance to medical regimens and patients who are considered potentially unreliable.
14. Unstable or serious co-existing medical condition, including potentially serious infection that would make the patient inappropriate for study participation, or any serious medical or psychiatric disorder that would interfere with the patient’s safety or informed consent. (No specific tests are required for confirmation of egilibility).
15. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Tumor response after 6 month of treatment according to modified RECIST criteria. |
|
| 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 | 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 | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Femara 2,5 mg each patient, additionaly according to randomization: Zometa up to 4 mg daily |
|
| 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.8.5 | 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 | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
The study will be terminated in case of non-tolerable SAEs which no longer justify the treatment of patients with study medication (monotherapy or combination therapy) from a medical and/or ethical point of view.
An interim analysis will be conducted after the treatment of 200 patients. The purpose of the interim analysis is to discontinue the study due to futility and not due to efficacy. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
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