| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
This study will be a head to head comparison of letrozole versus anastrozole in the adjuvant
treatment of high risk
patients. Post-menopausal patients who recently have undergone their primary surgery for their
breast cancer are targeted patient population. They must also have hormone positive disease and
have lymph node positive disease. The primary surgery could have been a total mastectomy,
lumpectomy or quadrantectomy for primary
breast cancer.
|
|
| 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 compare the rate of disease free survival (DFS) at 5 years in postmenopausal women with hormone
receptor
and lymph node positive breast cancer randomized between letrozole and anastrozole.
|
|
| E.2.2 | Secondary objectives of the trial |
-To compare the general safety between the two treatment arms.
-To compare the two treatment groups in a descriptive manner with the
other indicators of efficacy including overall survival, time to
development of distant metastases, time to development of contra
lateral breast cancer and distant disease-free survival.
-Compare the effect of treatment on serum lipid profiles between
treatment arms, and describe the incidence of cardiovascular events in
each treatment arm
-Describe the incidence of bone fractures in each treatment arm |
|
| 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 |
Correlative science studies, including immunohistochemical analyses, tumor RNA profiling, tissue
microarray
analysis, estradiol, estrone and estrone sulphate levels, pharmacogenetics and proteomics, will be
conducted in a
subset of patients to better understand which predictors define the course of each breast cancer
patient's disease.
|
|
| E.3 | Principal inclusion criteria |
1. Provision of written informed consent.
2. Patient must be female.
3. Patient must have undergone primary breast cancer surgery with
institutional standard axillary dissection such as the following:
• A total mastectomy with institutional standard axillary nodal
dissection.
• A lumpectomy or a quadrantectomy with institutional standard axillary
dissection with breast radiotherapy (may be deferred until
chemotherapy is completed) in accordance with breast preservation.
• Treatment of the breast cancer following diagnosis may have included
any of the following: post-lumpectomy/quadrantectomy regional
radiotherapy, post-mastectomy locoregional radiotherapy, postoperative
chemotherapy, and trastuzumab.
4. The tumor must have been pathologic or clinical stage IIA to IIIC
invasive carcinoma of the breast documented by core needle or open
biopsy. Patients with Paget's disease of the nipple are eligible.
5. The date of randomization must be no more than:
• 12 weeks from completion of surgery or adjuvant chemotherapy
• Investigators are encouraged to enroll patients as soon as possible
after the completion of adjuvant chemotherapy.
Note adjuvant radiation and endocrine therapy e.g. letrozole and
anastrozole can be given at the same time as radiotherapy due to nonoverlapping
toxicity profile.
6. Presence of node positive disease.
Positive node is defined as the presence of at least micro metastasis
greater than 0.2 mm according to the AJCC Breast Staging Criteria
Edition 6.
7. Patients who have had neoadjuvant chemotherapy are eligible.
Positive lymph node involvement can be defined either prior to
neoadjuvant chemotherapy or at the time of surgery following their
neoadjuvant therapy. Lymph node positivity would bedefined as the
following: REFER TO CURRENT PROTOCOL FOR DETAILS
8. Presence of occult axillary lymph node (pN1-pN3b) with no evidence
of primary breast tumor (T0) or only DCIS identified and whose
metastases are isolated to axillary lymph nodes associated with the
following:
• Lymph node reflects invasive adenocarcinoma histology
• Measurement of ER, PgR, and HER2 must be performed on initial lymph
nodes that were biopsied.
• Complete staging evaluation required as per standard institutional
practices to exclude any other primary sites of disease, including
metastatic disease.
9. Bilateral, synchronous breast cancer is allowed provided at least one
of the primary tumors meets the eligibility criteria.
10. Hormone receptor-positive tumors, defined as any detectable
estrogen or progesterone receptor expression by institutional standards.
Patients who are PgR positive and ER negative are eligible for the trial.
Tumor slides should be submitted for central evaluation of hormone
receptor status as per Section 3.5.3.3.7 and Post-text Supplement 2.
11. HER2 status must be known.
Note if possible tumor slides should be submitted for central
confirmation of hormone and HER2 receptor status as per Section
3.5.3.3.7 and Post-text Supplement 2.
12. Physical and laboratory examinations, as per standard institutional
practice, should be obtained at the time of definitive surgery to
demonstrate there is no evidence of metastatic
or recurrent disease.
13. Patients must have an WHO performance status of 0 or 1 (0 = fully
active, able to carry on all pre-disease performance without restriction;
1 = restricted in physically strenuous
activity but ambulatory)
14. Patients must be postmenopausal at the time of initial diagnosis. For
study purposes, postmenopausal is defined as: REFER TO CURRENT
PROTOCOL FOR DETAILS
15. WBC ≥ 3.0 x 109/L and platelets ≥ 100 x 109/L.
16. AST/SGOT or ALT/SGPT ≤ 3 times ULN.
17. Serum creatinine ≤ 2 times ULN.
18. Ability to swallow whole tablets. |
|
| E.4 | Principal exclusion criteria |
1. Presence of metastatic disease or inflammatory breast cancer as documented by dermal lymphatic
invasion.
2. Presence of metachronous bilateral breast cancer.
3. Previous or concomitant other (non-breast cancer) malignancy within the previous 5 years except
in situ carcinoma of the cervix or curatively treated basal and squamous cell carcinoma of the
skin.
4. Presence of other non-malignant systemic diseases which may prevent prolonged follow-up.
5. Received neoadjuvant endocrine therapy
6. Hormone replacement therapy (HRT) other than Estring®, Vagifem® or low dose estrogen vaginal
cream, not stopped at least 4 weeks before randomization. Thyroid replacement, insulin or other
anti-diabetic medication are permitted to be continued.
7. Adjuvant anti-estrogen therapy for more than 1 month immediately following surgery, radiotherapy
and/or chemotherapy.
8. Breast cancer chemoprevention with anti-estrogens if less than 18 months between stopping and
diagnosis of breast cancer.
9. Severe hepatic dysfunction defined as Child-Pugh grade C. REFER TO TABLE 3-2 IN THE CURRENT
PROTOCOL
10. Therapy with any hormonal agent such as raloxifene for management of osteoporosis. (Patients
are eligible
only if these medications are discontinued 4 weeks prior to randomization.)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| every 6 months during follow-up |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| every 6 months during follow-up |
|
| 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 | Yes |
| 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 | 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) | Yes |
| 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
| No |
| 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.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
|
English The trial ends when 959 DFS events have occurred but no later than
approximately April 2018. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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