ANZ 1401 (ELIMINATE) Randomised phase II trial of neoadjuvant chemotherapy +/- concurrent aromatase inhibitor endocrine therapy to down-stage large oestrogen receptor positive breast cancer
ANZ 1401 (ELIMINATE) - Women with ER-positive, HER2-negative, grade 2/3 invasive breast cancer > 20 mm in a Phase II study randomized to receive standard neoadjuvant chemotherapy concurrently with an aromatase inhibitor compared with standard neoadjuvant chemotherapy only to compare the rate of downstaging to pathological stage 0 or 1A.
Breast Cancer Trials
134 participants
May 25, 2015
Interventional
Conditions
Summary
This study aims to add hormone treatment (aromatase inhibitor (letrozole)) to standard neoadjuvant chemotherapy and find out if this treatment is more effective in reducing the size of large breast cancers before surgery. More effective down-staging of large breast cancers before surgery increases the likelihood of achieving a complete surgical resection and can increase the rate of breast conserving surgery. Who is it for? You may be eligible for this study if you have ER-positive, HER2-negative invasive breast cancer that is > 20 mm in size, and is suitable for neoadjuvant chemotherapy with the aim to have surgery - either breast conservation surgery or mastectomy. Trial Details Participants will be planned for 18-24 weeks (or 6 to 8 three-weekly cycles) of chemotherapy before surgery (mastectomy or breast conserving surgery). Participants will be randomised at a ratio of 2:1 to either standard chemotherapy plus letrozole (before surgery) or to standard chemotherapy alone (before surgery). The participants randomised to standard chemotherapy plus letrozole treatment will take a letrozole tablet once per day at the same time they are having their chemotherapy treatment. Participants who are pre- or perimenopausal will also have a goserelin implant inserted under their skin to stop their ovaries producing oestrogen. All participants will have pre-treatment bilateral mammogram, ipsilateral breast and axillary ultrasound, research core biopsies and marking of the tumour, MRI of the breast and serial research blood tests. Additional research core biopsies will be taken prior to the 3rd chemotherapy cycle (between week 6 and week 7 if receiving weekly chemotherapy). Participants will be clinically assessed prior to each chemotherapy cycle or once every 3 weeks if receiving weekly chemotherapy. A post-treatment breast MRI will be done prior to surgery. Research biopsies of the breast tumour are required from the tumour at surgery. The effectiveness of adding the hormone treatment (letrozole) will be assessed by the size of the tumour at surgery. There will be one post-surgery follow-up visit.
Eligibility
Inclusion Criteria25
- Female >= 18 years.
- Intact histologically confirmed grade 2 or 3 invasive breast cancer on core biopsy.
- ER positive (>= 10% cells) on core biopsy.
- HER2 negative (IHC 0 or 1+ or ISH negative breast cancer on core biopsy). Negative ISH test is required if HER2 testing shows IHC 2+.
- The primary breast tumour measures > 20 mm by ultrasound and/or mammogram (clinical stage cT2-4). In the case of a multifical tumour (defined as the presence of two or more foci of cancer within the same breast quadrant), the largest lesion must be >20 mm.
- Clinical stage II or stage III disease as defined by Protocol Appendix D.
- Clinically and pathologically suitable for neoadjuvant chemotherapy of at least 18 weeks duration (i.e. minimum of 6 three-weekly cycles) that includes an anthracycline and a taxane.
- Willing to undergo breast core biopsies for research purposes on 2 occasions prior to surgery.
- Surgeon has a realistic expectation that either mastectomy or breast conservation surgery will be feasible at the end of neoadjuvant treatment to achieve a complete surgical resection.
- Patient and surgeon agree to axillary node dissection if clinical or radiologic examination after neoadjuvant therapy suggests lymph node involvement
- Patient and surgeon agree in cases of cytologically positive (FNA/core) axilla at diagnosis, that converts after neoadjuvant therapy to a negative axilla on clinical examination and imaging, that an axillary dissection will be performed unless 3 sentinel nodes can be removed using dual mapping technique.
- Any menopausal status. A serum or urine test must be carried out on all women of child-bearing potential (pre- or perimenopausal status) to exclude pregnancy. Patients must cease all hormonal contraception and hormone replacement therapies from the time of informed consent. Patients of child-bearing potential must agree to use at least one form of adequate non-hormonal contraception (e.g. barrier method of birth control; abstinence) from the time of signing informed consent.
- Patients will be clinically defined as pre- or perimenopausal unless one of the following criteria is met for the definition of postmenopausal: Patient with intact uterus and ovaries and age > 55 years and amenorrhea for > 1 year; Surgical bilateral oophorectomy; Postmenopausal oestradiol/LH/FSH levels.
- Patient has adequate bone marrow function:
- Neutrophil count > 1.5 x 10^9/L
- Platelets >= 100 x 10^9/L
- Haemoglobin > 100 g/L.
- Patient has adequate hepatic function:
- Bilirubin < upper limit of normal (ULN) for institution (except Gilbert’s disease)
- ALT/AST <= 2 x ULN for institution
- Alkaline phosphatase <= 2.5 x ULN for institution.
- Patient has adequate renal function:
- Creatinine within normal institutional limits OR
- eGFR > 60mL/min/1.73m^2
- Patient is able to provide signed informed consent, including consent for collection and storage of serial biological specimens
Exclusion Criteria20
- Prior incisional biopsy or excision of primary breast tumour.
- Patients with an occult breast primary tumour or primary breast tumour that is not radiologically measurable.
- Sentinel lymph node biopsy or axillary node removal prior to neoadjuvant therapy. Ultrasound-guided FNA cytology and/or core biopsy of suspicious axillary nodes is recommended at baseline.
- Patients with grade 1 tumours.
- Patients with bilateral breast cancer.
- Multicentric breast cancer (the presence of more than one tumour in different quadrants of the breast).
- Male patients.
- Previous invasive breast cancer.
- Prior chemotherapy for breast or other invasive cancer.
- Previous radiotherapy to the currently affected breast.
- Pregnant or breast feeding (discontinuation of breast feeding prior to commencing study treatment is acceptable).
- Patients with any in situ hormonal formulations for contraception or HRT (e.g. Mirena IUD, Depot Provera, contraceptive implants, HRT implants), unless removed prior to randomisation.
- Patients planning to use GnRH during chemotherapy (with the goal of protecting fertility) regardless of randomised treatment allocation.
- Previous therapy with SERMs or Aromatase inhibitors.
- Distant metastases. Investigations to detect distant metastases are not mandatory but are recommended for patients with clinical stage 3 disease. Lesions of uncertain significance on staging investigations which are not planned for any additional pre-operative imaging after completion of neoadjuvant therapy will NOT result in exclusion from the study provided the intention of the clinician is to proceed with breast surgery with curative intent after neoadjuvant therapy.
- Cardiac contraindication to an anthracycline. Baseline cardiac testing is not required but is advisable if cardiac risk factors are present.
- Neurologic contraindication to taxane.
- Concomitant untreated other invasive malignancy (apart from breast cancer), with the exception of basal or squamous cell carcinoma of the skin
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, or any psychiatric disorder that prohibits obtaining informed consent.
- Administration of any investigational drug(s) from 2 weeks before randomisation until the end of study visit.
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Interventions
Standard neoadjuvant chemotherapy plus aromatase inhibitor endocrine therapy (letrozole). Pre- and perimenopausal women will also receive goserelin. Participants randomised to the experimental chemo-endocrine arm will receive neoadjuvant endocrine therapy as follows: * Postmenopausal participants randomised to experimental arm: - Administration of oral letrozole 2.5 mg daily will commence as soon as feasible following randomisation, prior to initiation of chemotherapy and continue after completion of chemotherapy until the day of surgery. * Pre- and perimenopausal participants randomised to experimental arm: - The first goserelin implant (3.6 mg) will be injected as soon as feasible following randomisation, prior to initiation of chemotherapy and repeated every 4 weeks (+/- 3 days) until the day of surgery. - Oral letrozole 2.5 mg daily will commence with the second goserelin injection (i.e. 4 weeks after the first goserelin injection) and continue after completion of chemotherapy until the day of surgery. Letrozole compliance will be measured via blood test.
Locations(1)
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ACTRN12614000515695