A Randomized, Open-label, Multicenter, Phase II Study Comparing the Effects on Proliferation and the Efficacy and Tolerability of Fulvestrant (FASLODEX™) 500 mg with Fulvestrant (FASLODEX™) 250 mg when given as Neoadjuvant Treatment in Postmenopausal Women with Estrogen Receptor Positive Breast Cancer (T2, 3, 4b, N0-3, M0) - NEWEST – Neoadjuvant Endocrine therapy for Women with Estrogen Sensitive Tumors

• Register: EUCTR
• Last refreshed on: 1 May 2012
• Main ID: EUCTR2004-003617-16-DE
• Date of registration: 30/12/2005
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: A Randomized, Open-label, Multicenter, Phase II Study Comparing the Effects on Proliferation and the Efficacy and Tolerability of Fulvestrant (FASLODEX™) 500 mg with Fulvestrant (FASLODEX™) 250 mg when given as Neoadjuvant Treatment in Postmenopausal Women with Estrogen Receptor Positive Breast Cancer (T2, 3, 4b, N0-3, M0) - NEWEST – Neoadjuvant Endocrine therapy for Women with Estrogen Sensitive Tumors
• Scientific title: A Randomized, Open-label, Multicenter, Phase II Study Comparing the Effects on Proliferation and the Efficacy and Tolerability of Fulvestrant (FASLODEX™) 500 mg with Fulvestrant (FASLODEX™) 250 mg when given as Neoadjuvant Treatment in Postmenopausal Women with Estrogen Receptor Positive Breast Cancer (T2, 3, 4b, N0-3, M0) - NEWEST – Neoadjuvant Endocrine therapy for Women with Estrogen Sensitive Tumors
• Date of first enrolment: 02/02/2006
• Target sample size: 200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2004-003617-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Comparison of two doses, 250 mg and 500 mg of fulvestrant

Countries of recruitment

Germany, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Provision of written informed consent.
2. Histologically/cytologically confirmed invasive breast cancer, ER positive as defined by the local laboratory
3. Operable or potentially operable locally advanced tumor (T2, 3, 4b, N0-3, M0). The largest diameter of the tumor as measured by ultrasound or by MRI must be = 2 cm. Patients with two measurable nodules will be eligible as long as both lesions are biopsied and have similar histology and are both ER positive.
4. Postmenopausal woman, defined as a woman fulfilling any 1 of the following criteria:
· Age = 60 years
· Age = 45 years with amenorrhea =12 months with an intact uterus
· Having undergone a bilateral oophorectomy
· FSH and estradiol levels in postmenopausal range (utilizing ranges from the testing laboratory facility).
5. Willingness to undergo biopsy at baseline and at 4 weeks and surgery at 16 weeks
6. WHO performance status 0, 1 or 2
For inclusion in the genetic component of the study, patients must fulfill the following criteria:
1. Provision of informed consent for genetic sampling and analyses
If a patient declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Inoperable due to satellite skin nodules or true inflammatory carcinoma.
2. Multifocal disease (> 2 major tumor nodules). Patients with more than one primary tumor will be excluded.
3. 3. Presence of metastatic disease as defined by the most current guidelines of the American Joint Committee on Cancer (AJCC). Metastatic evaluation should be performed according to the usual guidelines of the institutions. It is recommended that the following evaluations should be done:
· Chest X-ray
· Liver function tests
· CBC with differential cell count and platelet count.
· Abdominal CT scan if liver function tests significantly elevated
· CT scan of the chest and abdomen for clinical stage = T3, or = N1
· Bone scan if bony discomfort, elevated serum alkaline phosphatase, = T3 or =N1 clinical disease
· Bilateral mammograms
4. Any previous treatment for breast cancer
5. Unwillingness to stop taking any drug known to affect sex hormonal status (including HRT), or a patient in whom it would be inappropriate to stop
6. Current or prior malignancy within previous 3 years (other than adequately treated basal cell or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix)
7. Any of the following laboratory values:
· Platelets < 100 x 109 / L
· Total bilirubin > 1.5 x ULRR
· ALT or AST > 2.5 x ULRR
8. Any severe concurrent condition that would preclude surgery or that would jeopardize compliance with the protocol, eg, uncontrolled cardiac disease or uncontrolled diabetes mellitus
9. Patients known to be HIV, hepatitis B or C positive are not eligible because of the potential to confound the study endpoints, although patients will not be routinely screened for HIV, hepatitis B or C
10. History of :
· bleeding diathesis (ie, disseminated intravascular coagulation [DIC], clotting factor deficiency) or
· long-term anticoagulant therapy (other than antiplatelet therapy and low dose warfarin – see Section 3.7)
11. History of hypersensitivity to castor oil
12. Treatment with a non-approved or experimental drug within 4 weeks before randomization



Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Postmenopausal Women with Estrogen Receptor Positive Breast Cancer (T2, 3, 4b, N0-3, M0)

Intervention(s)

Product Name: Faslodex 250 mg/5 ml solution for injection
Product Code: EU/1/03/269/0001
Pharmaceutical Form: Solution for injection
INN or Proposed INN: fulvestrant
CAS Number: 129453-62-8
Current Sponsor code: ZD9238
Other descriptive name: ICI 182780
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Main Objective: To compare the effects of fulvestrant 500 mg and fulvestrant 250 mg on the proliferation marker Ki67 at 4 weeks

Secondary Objective: Compare effects of fulvestrant 500 mg and 250 mg on:
- the down-regulation of ER and PgR expression
- proliferation marker Ki67
- clinical, radiological and pathological tumor responses
Correlate response after 16 weeks of treatment to biological correlates detected after 4 and 16 weeks of treatment
Compare the actual surgery performed
Compare the effects of fulvestrant 500 mg and 250 mg on:
- endometrial thickness and uterine dimensions
- serum bone markers
Assess:
- correlation between changes in Ki67 LI and changes in ER and PgR expression
- pharmacokinetics of fulvestrant
- relationship between the pharmacokinetics markers (AUC, Cmax) and dynamic markers of downregulation and proliferation
Compare the tolerability of fulvestrant 500 mg with that of fulvestrant 250 mg

Primary end point(s): Efficacy: Comparison of fulvestrant 250 mg and 500 mg by measuring tumour markers at 4 and 16 weeks

Pharmacokinetics and Safety

Secondary ID(s)

D6997C00003 (9238IL/0065)