| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of cancer treatment-related bone loss in postmenopausal women with resected stage I-IIIa hormone receptor positive breast cancer, who will receive letrozole as adjuvant therapy. |
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| MedDRA Classification |
| 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 monitor the BMD in the lumbar spine (L1 to L4), as measured by Q-CT in postmenopausal women with hormone receptor positive breast cancer 12 months after registration. |
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| E.2.2 | Secondary objectives of the trial |
1. To monitor the BMD in the lumbar spine (L1 to L4) as measured by Q-CT 24, 36
and 60 months after registration.
2. To determine the incidence rate of all clinical fractures at 3 years after registration.
3. To evaluate the general safety of the treatment.
4. To describe the time to disease recurrence/relapse at 5 years after registration.
5. To describe overall survival at 5 years after registration.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must fulfill all of these inclusion criteria:
1. Signed written informed consent.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 2
3. Postmenopausal status defined by one of the following:
• Age >/= 55 years with cessation of menses.
• Age <55 but no spontaneous menses for at least 1 year.
• Age <55 and spontaneous menses within the past 1 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 (<5ng/dL) or according to the definition of “postmenopausal range” for the laboratory involved.
• Bilateral oophorectomy.
4. Hormone receptor positive defined as ER and/or PgR >/= 2 (Remmele/Stegner)
5. Patients with a baseline lumbar spine BMD T-score at or above - 2.0 SD.
6. Adequately diagnosed and treated invasive breast cancer defined as:
• Patients with invasive breast cancer whose tumor can be removed by an appropriate surgical procedure such as mastectomy or breast conserving surgery and who receive, if appropriate, additional local (e.g. radiotherapy) and/or systemic (i.e. adjuvant chemotherapy) treatments, according to best practice.
• Patients may have also received prior neoadjuvant chemotherapy. Prior neoadjuvant chemotherapy must be completed before entering the patient onto the present protocol.
• The date of registration must be no more than:
a. 4 weeks from completion of surgery (in case of surgery alone), or
b. 4 weeks from completion of surgery (in case of surgery + radiotherapy) or
c. 4 weeks after completion of adjuvant chemotherapy (if planned to be given before the endocrine therapy) or
d. 4 weeks after completion of chemotherapy followed by radiation.
Completion of chemotherapy is defined as completion of the last full course including recovery time.
• When the plan is to give concomitant adjuvant chemotherapy and hormonotherapy, the treatment should start at the same time and the date of registration must be no more than 4 weeks from completion of surgery;
• Patients must have no clinical or radiological evidence of distant metastasis, and no other concomitant malignancy.
7. Patients must be able to swallow the study medication and have adequate unassisted oral intake to maintain a reasonable state of nutrition.
8. Life expectancy of at least 12 months from registration.
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| E.4 | Principal exclusion criteria |
1. Patients with any clinical or radiological evidence of distant spread of their disease at any point before registration.
2. Patients with invasive bilateral breast cancer.
3. Patients with any clinical or radiological evidence of existing fracture in the lumbar spine and/or total hip.
4. Patients with a history of fracture with low-density or no associated trauma.
5. Patients who have started adjuvant hormonal therapy or who have completed adjuvant hormonal therapy prior to registration.
6. Patients who have received any endocrine therapy within the past 12 months (other than neoadjuvant tamoxifen or torimefene, insulin and/or anti-diabetic medications, and thyroid hormone replacement). Hormone replacement therapy must be discontinued at least 4 weeks prior to registration.
7. Patients currently receiving oral bisphosphonates. Oral bisphosphonates must be discontinued within 3 weeks of baseline evaluations.
8. Patients who have received prior treatment with systemic corticosteroids within the past 12 months (short term corticosteroid therapy, e.g. to prevent/treat chemotherapy-induced nausea/vomiting is allowed).
9. Patients with prior exposure to anabolic steroids or growth hormone within the past 6 months.
10. Treatment with tibolone must be discontinued at least 4 weeks prior to registration.
11. Any prior use of parathyroid hormone (PTH) for more than 1 week.
12. Prior use of systemic sodium fluoride for > 3 months during the past 2 years.
13. Patients currently treated with any drugs known to affect the skeleton (e.g., calcitonin, mithramycin, or gallium nitrate) within 2 weeks prior to registration.
14. Patients with previous or concomitant malignancy (not breast cancer) within the past 5 years EXCEPT adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix. Patients who have had a previous other malignancy must have been disease-free for five years.
15. Patients with other non-malignant systemic diseases including uncontrolled infections, uncontrolled type 2 diabetes mellitus, uncontrolled thyroid dysfunction, cardiovascular, renal, hepatic, and lung diseases which would prevent prolonged follow-up. Patients with previous history of thrombosis or thromboembolism can be included only if suitable for prolonged follow-up and not on steroids. Patients with a known history of HIV are excluded.
16. A calculated creatinine clearance < 30 ml/minute.
Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula:
CrCl= [140-age (years)] x weight (kg) {x 0.85 for female patients}
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[72 x serum creatinine (mg/dL)]
17. 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.
18. Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants).
19. History of diseases with influence on bone metabolism, such as Paget’s disease, Osteo-genesis Imperfecta, and primary or secondary hyperthyroidism within the 12 months prior to study entry.
20. Patients with baseline lumbar spine BMD T-score below –2.0 SD.
21. Known hypersensitivity to zoledronic acid or other bisphosphonates.
22. Mental illness that precludes the patient from giving informed consent.
23. WBC </= 3.0 x 109/L or granulocytes </= 1.5 x 109/L, platelets </= 100 x 109/L.
24. AST/SGOT and/or ALT/SGPT >3ULN in combination with other laboratory and clinical abnormalities indicating liver insufficiency to a degree that precludes dosing with letrozole (Child-Pugh grade C).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of the study is to estimate the influence of Zoledronic acid on BMD (DXA) measured in lumbar spine (L1 to L4), as measured by Q-CT in postmenopausal women with hormone receptor positive breast cancer 12 months after registration.
BMD (DXA) will be evaluated at baseline and at 12 months after start of treatment. The difference of both measured values of BMD describes the effect of the treatment and constitute the primary efficiacy variable.
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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 | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Information not present in EudraCT |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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 | 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 | 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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| Patients will be treated on study until disease recurrence or for a maximum of 5 years. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
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