ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12614000515695

Ethics application status

Approved

Date submitted

12/05/2014

Date registered

15/05/2014

Date last updated

21/02/2024

Date data sharing statement initially provided

5/03/2019

Date results information initially provided

5/03/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

ANZ 1401 (ELIMINATE) Randomised phase II trial of neoadjuvant chemotherapy +/- concurrent aromatase inhibitor endocrine therapy to down-stage large oestrogen receptor positive breast cancer

Scientific title

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.

Secondary ID [1]

ANZ 1401

Universal Trial Number (UTN)

Trial acronym

ELIMINATE

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Grade 2/3 ER-positive, HER2-negative Invasive Breast Cancer > 20 mm

Condition category

Condition code

Cancer

Breast

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

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.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Standard neoadjuvant chemotherapy:

This will be an anthracycline and taxane containing regimen of 18-24 weeks duration. For sequential regimens, order of the taxane and anthracycline is at the sites’ discretion. Examples include:
AC (or FEC) x 4 - weekly paclitaxel x 8-12 (or reverse sequence)
AC (or FEC) x 4 - docetaxel x 4 (or reverse sequence)
FEC X 3 - docetaxel x 3 (or reverse sequence)

Control group

Active

Outcomes

Primary outcome [1]

Rate of downstaging of invasive cancer to pathologic stage 0 or 1A (ypT0-1 ypN0 i.e. tumour <=20 mm and node negative). The ypT is measured as the largest single focus of invasive tumour

Timepoint [1]

At the time of surgery

Secondary outcome [1]

The proportion of patients with pathological complete response (pCR) in both the breast and axilla (pCR: ypT0/is ypN0).

Timepoint [1]

At the time of surgery

Secondary outcome [2]

The proportion of patients with pathologic complete response (pCR) in the breast (yPT0/is).

Timepoint [2]

At the time of surgery

Secondary outcome [3]

Median breast tumour volume percentage decrease as determined by MRI.

Timepoint [3]

At the end of neoadjuvant treatment

Secondary outcome [4]

Rate of breast conserving surgery (BCS) with adequate radial margins

Timepoint [4]

At the time of surgery

Secondary outcome [5]

Proportion of patients who would have required mastectomy to surgically resect at baseline but were down-staged and deemed suitable for BCS (even if not chosen by patient) after neoadjuvant therapy

Timepoint [5]

At the time of surgery

Secondary outcome [6]

Serious adverse event (SAE) rates in the two study arms. SAEs are reported using the SAE form and will be clinically reviewed.

A SAE is any adverse event (experience) or reaction or any untoward medical occurrence that at any dose fulfils one of the following:
* Is fatal (results in death)
* Life threatening (Note: the term “life-threatening” in the definition of “serious” refers to an event in which the patient was at risk of death at the time of the event. It does not refer to an event which could hypothetically have caused death had it been more severe)
* Required patient hospitalisation or prolongation of existing hospitalisation (Note: “inpatient hospitalisation” refers to an unplanned, overnight hospitalisation)
* Results in persistent or significant disability/incapacity
* Is a congenital anomaly/birth defect
* Is medically significant or requires intervention to prevent one or other of the outcomes listed above.

Events not considered to be serious adverse events for the ANZ 1401 clinical study are hospitalisations occurring under the following circumstances:
a) Planned before entry into the clinical study for a pre-existing condition that is unrelated to the studied indication
b) For elective treatment of a condition unrelated to the studied indication or its treatment
c) Not resulting in admission (unless fulfilling the criteria of serious given above)
d) General care or part of the normal treatment of the studied indication, not associated with any deterioration in condition
e) Gastrointestinal toxicity due to chemotherapy
f) Febrile neutropaenia due to chemotherapy.

Timepoint [6]

42 months after study start

Secondary outcome [7]

Translational objectives will be finalised after collection of samples is complete as the relevant biomarkers may evolve over time. Tumour biomarkers currently considered relevant to study include: Ki67, c-Myc, cyclin D1, Bcl-2, p21 and p27. Multigene assay testing of tumours may be performed, if available. Other translational biomarkers (i.e. PI3KCA mutations) may be studied as deemed relevant.

Timepoint [7]

42 months after study start

Secondary outcome [8]

Proportion of patients down-staged to ypT0-1 ypN0 (largest contiguous focus residual invasive cancer <= 20 mm and node negative) and with a total distance over which residual invasive tumour extends also < 20 mm in maximum dimension (relevant when multiple scattered tumour foci remain)

Timepoint [8]

At time of surgery

Secondary outcome [9]

Proportion of patients with node negative disease at definitive surgery (ypN0), excluding ypN0(i+)

Timepoint [9]

At time of surgery

Secondary outcome [10]

The overall objective radiologic response rate (complete plus partial) in the breast (CR + PR) as determined by MRI.

Timepoint [10]

After completion of chemotherapy and just prior to surgery

Eligibility

Key inclusion criteria

* 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

Minimum age

18 Years

Maximum age

No limit

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

* 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.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Update
* Obtain written informed consent for participation in ANZ 1401, signed and dated by the patient and investigator.
* Verify eligibility
* Access the ANZ 1401 randomisation system (www.breastcancertrials.org.au) and perform randomisation
The method of randomisation will be minimisation stratified by clinical tumour stage and menopausal status.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Other design features

Phase

Phase 2

Type of endpoint/s

Efficacy

Statistical methods / analysis

This will be a randomised phase II study with randomisation 2:1 in favour of concurrent chemo-endocrine neoadjuvant therapy (experimental intervention arm) versus neoadjuvant chemotherapy alone (control arm). For a rate of down-staging to pathologic stage 0-1 of 30% in the control arm increased to 45% in the concurrent arm, this will require a sample size of 123. This will give a power of 80%, with 95% confidence.
Stratification will be by:
* Baseline clinical tumour stage – Clinical stage 2 (cT2N0-1 or cT3N0) versus Clinical stage 3 (cT2N2 or cT3N1-3 or cT4Nany) based on physical examination and imaging of breast and axilla.
* Menopausal status (postmenopausal versus pre/perimenopausal)

123 evaluable patients will be recruited over a period of up to 42 months. To be evaluable, patients must complete a minimum of 6 cycles of chemotherapy. Patients who withdraw from protocol assigned therapy prior to completion of 6 cycles of chemotherapy for reasons unrelated to tumour progression/unsatisfactory tumour response will be replaced.

There will be no long term follow-up of patients, with the primary study end point determined at time of surgery.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

31/03/2015

Actual

25/05/2015

Date of last participant enrolment

Anticipated

31/03/2018

Actual

30/04/2018

Date of last data collection

Anticipated

31/10/2018

Actual

27/02/2019

Sample size

Target

134

Accrual to date

Final

134

Recruitment in Australia

Recruitment state(s)

ACT,NSW,QLD,SA,TAS,WA,VIC

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Funding source category [2]

Other Collaborative groups

Name [2]

Breast Cancer Trials

Address [2]

PO Box 283
The Junction NSW 2291

Country [2]

Australia

Primary sponsor type

Other Collaborative groups

Name

Breast Cancer Trials

Address

PO Box 283
The Junction NSW 2291

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Adelaide Hospital Research Ethics Committee

Ethics committee address [1]

North Terrace
Adelaide SA 5000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

04/07/2014

Approval date [1]

19/08/2014

Ethics approval number [1]

HREC/14/RAH/277

Summary

Brief 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.

Trial website

www.breastcancertrials.org.au

Trial related presentations / publications

Public notes

Breast Cancer Trials formerly known as the Australia & New Zealand Breast Cancer Trials Group.

Contacts

Principal investigator

Name

Dr Nicholas Murray

Address

Medical Oncology
Royal Adelaide Hospital
North Terrace
Adelaide SA 5000

Country

Australia

Phone

+61 8 8222 2024

Fax

[email protected]

Contact person for public queries

Name

Ms Corinna Beckmore

Address

BCT
PO Box 283
The Junction NSW 2291

Country

Australia

Phone

+61 2 4925 5235

Fax

[email protected]

Contact person for scientific queries

Name

Dr Nicholas Murray

Address

Medical Oncology
Royal Adelaide Hospital
North Terrace
Adelaide SA 5000

Country

Australia

Phone

+61 8 8222 2024

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Anonymised Individual Patient Data (IPD) collected during the trial. The specific IPD to be shared (e.g. all data, published data, data of primary outcomes) will be as per the submitted research proposal and as assessed as appropriate by BCT.

When will data be available (start and end dates)?

Data will be made available for request after publication of the main/final study results; no end date.

Note that there may be additional circumstances preventing BCT from sharing requested data as outlined in the BCT Data Sharing Guidelines.

Available to whom?

Researchers who submit a research proposal and BCT Data Request Application, which is assessed by BCT to have appropriate scientific value. Refer to the BCT Data Sharing Guidelines

Available for what types of analyses?

To achieve the aims in the approved proposal.

How or where can data be obtained?

Subject to approval by Breast Cancer Trials [email protected] (refer to BCT Data Sharing Guidelines).

What supporting documents are/will be available?

Doc. No.	Type	Link	Other Details	Attachment
18383	Other	https://researchdata.edu.au/randomised-phase-ii-1401-eliminate/2836017	BCT Data Sharing Guidelines	366153-(Uploaded-07-12-2023-10-48-26)-Study-related document.docx
21697	Study protocol	https://doi.org/10.58080/rfsh-9s54
21698	Data dictionary	https://doi.org/10.58080/rfsh-9s54

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Conference abstract	No		https://www.annalsofoncology.org/issue/S0923-7534(... [More Details]	366153-(Uploaded-17-02-2023-10-26-10)-Other results publication.pdf

Documents added automatically

No additional documents have been identified.

Trial Review

Documents added manually

Documents added automatically