| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Premenopausal patients with histologically confirmed locally advanced breast cancer and with primary tumor of ER+/PgR+ and HER2 negative or not amplified. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with locally advanced breast cancer and who have not yet entered the menopause.Moreover patients have hormone receptor positive primary tumor and no overexpression of the growth recptor HER2. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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 evaluate the endocrine activity of neoadjuvant letrozole plus either degarelix or triptorelin. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
- Tolerability:
- Changes of Ki-67 proliferation marker
- The Preoperative Endocrine Prognostic Index (PEPI) score
- Best overall (disease) response: defined as best response
recorded from the start of treatment across all time points until
disease progression.
- Node negative disease at surgery.
- Breast-conserving surgery (BCS) rate.
- Patient reported symptoms (PRS) outcomes.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Female gender
•Premenopausal status determined locally:
-Estradiol (E2) above 54 pg/mL (or above 198 pmol/l),measured
≤14 days prior to randomization
-If estradiol (E2) is ≤54 pg/mL, but the patient cannot be
regarded as postmenopausal, estradiol testing should be
repeated to confirm eligibility
•Age ≥ 18 years
•Eastern Cooperative Oncology Group Performance Status
(ECOG PS) of 0 or1.
•Histologically confirmed invasive breast cancer:
-Primary tumor greater than 2 cm diameter, measured by clinical
examination and mammography or echography (cT2-4b)
-Any N
-No evidence of metastasis (M0)
•Primary tumor must have ER and PgR >50% of the cells
•Primary tumor must be HER2 negative or not amplified
•Hematopoietic status:
-Absolute neutrophil count ≥ 1.5 × 109/L,
-Platelet count ≥ 100 × 109/L,
-Hemoglobin ≥ 9 g/dL
•Hepatic status:
-Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the
case of known Gilbert’s syndrome, a higher serum total bilirubin
(< 2 × ULN) is allowed
-AST and ALT ≤ 2.5 × ULN
-Alkaline phosphatase ≤ 2.5 × ULN
•Renal status: Creatinine ≤ 1.5 × ULN
•Negative serum pregnancy test, within 2-weeks (preferably 7
days) prior to randomization. Pregnancy test has to be repeated
before treatment start if treatment does not start within 15
days of the previous test.
•The patient must be willing to use effective non-hormonal
contraception (barrier method – condoms, diaphragm – also in
conjunction with spermicidal jelly, or total abstinence) after the
pregnancy test and up to surgery. Oral, injectable, or implant
hormonal contraceptives or medicated IUD are not allowed.
•Prior fertility treatment is allowed but must have been stopped at
least 12 months before randomization
•The patient has completed the baseline patient-reported
symptoms questionnaire
•Written Informed Consent (IC) must be signed and dated by the
patient and the Investigator prior to randomization
•The patient has been informed of and agrees to data transfer
and handling, in accordance with national data protection
guidelines
•The patient accepts blood samples to be taken according to the
schedule in section 4.1 for the determination of the primary
endpoint
•The patient accepts to make tumor (biopsy and surgical
specimen) available for submission for central pathology review
and to conduct translational studies as part of this protocol
|
|
| E.4 | Principal exclusion criteria |
•Postmenopausal patients.
•Any hormonal treatment (either oral, injectable, implant, or
medicated IUD) in the previous 2 months.
•Presence of HER2/neu overexpression or amplification.
•Received any prior treatment for primary invasive breast cancer.
•Received any GnRH analog or SERM or AI within 12 months prior
to randomization
• Previous (less than 10 years) or current history of malignant
neoplasms, except for curatively treated:
-Basal and squamous cell carcinoma of the skin
-Carcinoma in situ of the cervix
-Carcinoma in situ of the bladder
•Diagnosis of inflammatory breast cancer
•Bilateral invasive breast cancer
•Known history of uncontrolled or symptomatic angina, clinically
significant arrhythmias, congestive heart failure, transmural
myocardial infarction uncontrolled hypertension (≥ 180/110),
unstable diabetes mellitus, dyspnea at rest, or chronic therapy
with oxygen
•Concurrent disease or condition that would make the subject
inappropriate for study participation or any serious medical
disorder that would interfere with the subject’s safety
•Unresolved or unstable, serious adverse events from prior
administration of another investigational drug
•Active or uncontrolled infection CTCAE v.4 grade 2 or higher
•Dementia, altered mental status, or any psychiatric condition
that would prevent the understanding or rendering of Informed
Consent
•Treatment with an investigational agent must have stopped at
least 30 days before randomization
•Pregnant or lactating women. Lactation has to stop before
randomization.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to optimal ovarian function suppression: time from first injection of degarelix or triptorelin to the first assessment of estradiol (E2) level in the range of optimal ovarian function suppression (<10 pg/mL) during the 6 cycles of neoadjuvant treatment. Data for patients who do not reach the targeted E2 level will be censored at the last E2 evaluation date. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
E2 levels will be determined at day 1 of the first treatment cycle before the administration of the first dose of degarelix or triptorelin (baseline), and thereafter at 24 and 72 hours, 7 days and 14 days after the first injection, and on day 1 of cycles 2 to 6 before the administration of degarelix or triptorelin.
|
|
| E.5.2 | Secondary end point(s) |
To evaluate:
- Tolerability: adverse events according to CTCAE version 4
- Changes of Ki-67 proliferation marker
- The Preoperative Endocrine Prognostic Index (PEPI) score
- Best overall (disease) response: defined as best response
recorded from the start of treatment across all time points until
disease progression.
- Node negative disease at surgery
- Breast-conserving surgery (BCS) rate.
- Patient reported symptoms (PRS) outcomes. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tolerability:The frequencies of AEs by type & worst grade experienced while on the neoadjuvant treatments will be summarized & tabulated by treatment arms
-Percentage change in Ki67 expression from pre-treatment to surgery (24 weeks) summarized for each treatment arm
-PEPI scores assessed at the time of surgery (24weeks) for both treatment arms
-Best overall response including complete response,partial response,stable disease&progressive disease is gathered at the end of 3rd (12weeks) & 6th (24weeks)cycle of each treatment arm
-Node negative disease at surgery(after 24weeks) descriptively summarized by treatment arm
-BCS at surgery after 24weeks
-PRS scores measured at baseline, day1 of cycle2 (8weeks) and cycle4 (16weeks) of triptorelin or degarelix administration & prior surgery |
|
| 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 | 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 | 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.8.2.4 | 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 | 7 |
| 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 | Yes |
| 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
|
| Randomization of 50 patients during approximately 24 months. The treatment and post-surgery evaluation will occur within 7 months. Thereafter patients will have no further follow-up. The end of the trial therefore will be approximately 31 months after randomization of the first patient. |
|
| 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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