Clinical trial NCT04584853: PreOperative Endocrine Therapy for Individualised Care With Abemaciclib
Official title: PreOperative Endocrine Therapy for Individualised Care With Abemaciclib
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Breast Cancer Female
Keywords: CDK4/6 inhibitor
ER+
HER2-
Lead sponsor: Institute of Cancer Research, United Kingdom
Sponsor class: OTHER
First posted: 2020-10-14
Enrollment: 2032
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: POETIC-A is a phase 3 trial which targets post-menopausal primary breast cancer patients with a high 5-year risk of relapse as determined by a high Ki67 after 2 weeks aromatase inhibitor therapy pre-surgery. Eligible patients will be randomised to standard adjuvant endocrine therapy alone or standard adjuvant endocrine therapy with a CDK4/6 inhibitor called abemaciclib.

Detailed description: In women with hormone sensitive early breast cancer, taking a hormone therapy (also known as endocrine therapy) for at least five years after surgery is very effective at reducing the risk of the cancer returning. However, for some women their cancer may eventually become resistant to these drugs. POETIC-A Registration part will identify those who have a higher risk of developing resistance to standard endocrine therapy (ET). At least 8000 women diagnosed with early stage breast cancer will enter the Registration stage from 80 centres. Study doctors will use aromatase inhibitors (AIs), a type of ET, to treat the cancer for between 2 weeks and 6 months before surgery. A sample will be taken from the cancer during surgery and the study laboratory will measure a biological marker called Ki67. If the level of Ki67 does not drop after 2 weeks of AI treatment, the patient is likely to be less sensitive to endocrine therapy, and the study doctor will explore additional treatments after surgery in the POETIC-A Treatment part. Everyone who agrees to join the Treatment stage (2032 patients) will be randomly put into one of the 2 treatment groups; Group1: ET only; or Group2: ET plus a new drug called abemaciclib. The first aim of the Treatment stage is to confirm whether abemaciclib given in combination with ET is more effective than giving ET alone in preventing the cancer coming back. The study laboratory will perform a second test on the cancer sample, called an AIR-CIS test. This test aims to find out if particular groups of patients based on their tumour biology are more suitable for treatment with abemaciclib. Patients in Group 2 will receive ET plus abemaciclib for 2 years. Patients in both groups will have regular study visits during this period.

Eligibility criteria: Registration Stage Inclusion Criteria:

1. Women determined to be postmenopausal according to established local criteria.
2. Diagnosed operable invasive breast cancer with a clinical/radiological tumour size ≥1.0cm\*
3. Grade 2 or 3 tumours
4. Preoperative full assessment completed (including bilateral breast examination and imaging with mammogram +/- ultrasound/MRI as performed locally).
5. Tumour ER positive. ER positivity is defined as \>/=1% cells staining positive (or equivalent Allred Score of ER \>/=3 out of 8).
6. Tumour HER2 negative or HER2 status unknown. HER2 negativity will be defined as per the 2018 ASCO/CAP updated guidelines. Patients whose HER2 status is pending/unknown at the time of registration will be allowed to register to the trial. However, please note that only patients who are confirmed to be HER2 negative will be eligible to join the randomised part.
7. Received or planned to receive 10 days to 6 months of anastrozole or letrozole prior to surgery.
8. Written informed consent to enter the registration stage of the trial and to donation of fresh tissue.
9. The patient has given written informed consent prior to any study-specific procedures and is willing and able to make herself available for the duration of the study and amenable and able to follow study schedule during treatment and follow-up and for the use of routinely collected electronic health and related records.

Registration Stage Exclusion Criteria:

1. Men and pre/perimenopausal women.
2. Intended or actual use of HRT or any other oestrogen-containing medication (including vaginal oestrogens) within 4 weeks prior to planned surgery). Note: patient with a Mirena coil in situ at the time of registration are not excluded.
3. Patients who commenced pre-surgical AI therapy \>6 months prior to surgery.
4. Prior endocrine therapy for breast cancer or breast cancer prevention.
5. Prior neoadjuvant chemotherapy for breast cancer.
6. Evidence of metastatic disease.
7. Locally advanced breast cancer not amenable to surgery.
8. Bilateral invasive breast cancer (excluding contralateral DCIS/LCIS).
9. Multiple unilateral tumours with different ER and/or HER2 status. Synchronous DCIS/LCIS, as well as multifocal disease with homogenous ER/HER2 status is allowed if at least one lesion is at least 1.0cm; the largest lesion should be used for sample collection and CRF completion. If ER/HER2 status of smaller foci is unknown at time of registration, patients can be registered; however, note that congruity of receptor status will need to be confirmed by the time of randomisation, unless smaller foci are \<10mm and receptor status is unknown.
10. Previous invasive breast cancer except for ipsilateral DCIS or LCIS treated \>5 years previously by locoregional therapy alone or contralateral DCIS/LCIS treated by locoregional therapy at any time.
11. Any invasive malignancy diagnosed within previous 5 years (other than non-melanoma skin cancer or cervical carcinoma in situ).
12. Any other medical condition likely to exclude the patient from subsequent randomisation stage. (See exclusion criteria: Eligibility for Randomisation).

Randomisation Stage Inclusion Criteria:

1. Patient previously consented and registered for screening component of POETIC-A.
2. Tumour HER2 negative. HER2 negativity will be defined as per the 2018 ASCO/CAP updated guidelines
3. Centrally confirmed Ki67 \>/=8% following 2 weeks of AI.
4. Patient is expected by the time of treatment initiation to have undergone definitive surgery for the primary breast tumour with clear radial margins as judged by the multidisciplinary team, and will have completed any adjuvant chemotherapy or radiotherapy (if prescribed).
5. Surgical staging of the axilla must have been undertaken by sentinel node biopsy, axillary sampling or dissection.
6. The patient is randomised in time for treatment to start no later than three months after completion of non-endocrine therapy (defined as the final fraction of radiotherapy, Day 1 of the final cycle of chemotherapy or the date of the final surgical procedure).
7. The patient is able to swallow oral medications (excluding transient side effects from adjuvant non-endocrine treatment, if randomised before the end of this treatment).
8. The patient intends to take adjuvant endocrine therapy for at least 5 years.
9. The patient has given written informed consent prior to any study-specific procedures (for the randomised intervention part), is willing to donate tissue from diagnostic biopsy, and is willing and able to make herself available for the duration of the study and to follow study schedule during treatment and follow-up and for the use of routinely collected electronic health and related records.

Randomisation Stage Exclusion Criteria:

1. Patient has received prior CDK4/6 inhibitor.
2. Patient is planned to receive adjuvant abemaciclib as standard of care.
3. Any patient with a history of VTE (for example, DVT of the leg or arm and/or PE) will be excluded. Patients with a history of venous catheter occlusion by thrombus that did NOT surround the catheter, and the lumen could be made patent by appropriate measures (for example, saline or thrombolytic agent), are not excluded.
4. The patient has a serious/or uncontrolled pre-existing medical condition(s) that, in the judgment of the investigator, is likely to preclude study treatment (such as severe renal impairment, \[for example, estimated creatinine clearance \<30 mL/min\], interstitial lung disease, severe dyspnoea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or pre-existing Crohn's disease or ulcerative colitis or a pre-existing chronic condition resulting in baseline Grade 2 diarrhoea).
5. The patient has a personal history of any of the following conditions: syncope of cardiovascular aetiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Exception: patients with controlled atrial fibrillation diagnosed more than 30 days prior to randomisation are not excluded.
6. The patient has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, prior to randomisation, or is currently enrolled in any other type of medical research (for example: medical device) judged by the Chief Investigator not to be scientifically or medically compatible with this study.
7. The patient has any known active systemic bacterial infections (that would be expected to require IV antibiotics at time of initiating study treatment), systemic fungal infection or detectable viral infection (such as known HIV positivity or with known active hepatitis B or C, e.g. hepatitis B surface antigen positive) which would be expected to preclude study treatment. Screening is not required for enrolment.
8. Evidence of metastatic disease or local recurrence.
9. Multiple unilateral tumours with different ER and/or HER2 status (DCIS/LCIS are permitted, and confirmation of congruent ER/HER2 status is not necessary for lesions less than 10mm).

Week 1 Day 1 Inclusion Criteria:

1. Patient must have undergone definitive surgery for the primary breast tumour with clear radial margins as judged by the multidisciplinary team.
2. Adjuvant chemotherapy, if prescribed, must have been completed prior to Week 1 Day 1, and patients must have recovered (Common Terminology Criteria for Adverse Events, version 5 \[CTCAE v5\] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to Week 1 Day 1. A washout period of a minimum of 28 days from day 1 of the last cycle of treatment is required.
3. Adjuvant radiotherapy, if prescribed, must have been completed prior to Week 1 Day 1, and patients must have recovered (Grade \</=1) from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and Week 1 Day 1.
4. Week 1 Day 1 is scheduled to take place no later than three months after completion of non-endocrine therapy (defined as the final fraction of radiotherapy, Day 1 of the final cycle of chemotherapy or the date of the final surgical procedure, whichever is latest).
5. The patient is able to swallow oral medications.
6. The patient has adequate organ function for all of the following criteria defined as: ANC \>/= 1.5 × 10e9/L (G-CSF cannot be administered to meet this ANC eligibility criterion); Platelets \>/= 100 × 10e9/L; Haemoglobin \>/= 8g/dL; Total bilirubin \</= 1.5 × ULN (Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted); ALT and AST \</= 3 × ULN

Week 1 Day 1 Exclusion Criteria:

1. Patient has received any CDK4/6 inhibitor therapy since randomisation.
2. Any newly occurring or diagnosed VTE since randomisation (for example, DVT of the leg or arm and/or PE). Note: patients with a history of venous catheter occlusion by thrombus that did NOT surround the catheter, and the lumen could be made patent by appropriate measures (for example, saline or thrombolytic agent), are not excluded.
3. Any newly occurring or diagnosed medical conditions since randomisation that, in the judgment of the investigator, would preclude participation in this study (such as severe renal impairment, \[for example, estimated creatinine clearance \<30 mL/min\], interstitial lung disease, severe dyspnoea at rest or requiring oxygen therapy, major surgical resection involving the stomach or small bowel, or condition resulting in baseline Grade 2 diarrhoea).
4. Any newly occurring or diagnosed cardiovascular conditions since randomisation such as: syncope of cardiovascular aetiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
5. Major surgery within 14 days prior to Week 1 Day 1.
6. The patient has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, prior to Week 1 Day 1, or is currently enrolled in any other type of medical research (for example: medical device) judged by the Chief Investigator not to be scientifically or medically compatible with this study.
7. Any active systemic bacterial infections (requiring IV antibiotics at time of Week 1 Day 1), systemic fungal infection or detectable viral infection (such as known HIV positivity or active hepatitis B or C, e.g. hepatitis B surface antigen positive). Screening is not required for initiation of treatment.
8. Evidence of metastatic disease or local recurrence

Primary outcomes:
measure: Time to tumour (local or distant disease) recurrence
timeFrame: from randomisation until tumour recurrence or patient death, assessed up to 5 years
Secondary outcomes:
measure: Relapse-free-survival
timeFrame: from randomisation until relapse or patient death, assessed up to 5 years
measure: Time to distant recurrence
timeFrame: from randomisation until distant recurrence or patient death, assessed up to 5 years
measure: Breast cancer specific survival
timeFrame: from randomisation until patient death from breast cancer, assessed up to 5 years
measure: Overall survival
timeFrame: from randomisation until patient death, assessed up to 5 years
measure: Patient reported quality of life
timeFrame: 5 years from randomisation
measure: Grade 3/4 Adverse Events, SAEs and hospitalisations
timeFrame: from treatment start up to 28 days after treatment discontinuation
measure: Treatment related deaths
timeFrame: 5 years from randomisation
Other outcomes:
Locations:
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
state: Cornwall
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
state: Devon
city: King's Lynn
country: United Kingdom
facility: Queen Elizabeth Hospital
state: England
city: Swindon
country: United Kingdom
facility: Great Western Hospital
state: England
city: Northampton
country: United Kingdom
facility: Northampton General Hospital
state: Northants
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
state: Northern Ireland
city: Larbert
country: United Kingdom
facility: Forth Valley Royal Hospital
state: Scotland
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
state: Surrey
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Ashington
country: United Kingdom
facility: Wansbeck General Hospital
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
city: Bath
country: United Kingdom
facility: Royal United Hospital Bath
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Boston
country: United Kingdom
facility: Pilgrim Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: Burnley
country: United Kingdom
facility: Burnley General Hospital
city: Doncaster
country: United Kingdom
facility: Doncaster Royal Infirmary
city: Dumfries
country: United Kingdom
facility: Dumfries and Galloway Royal Infirmary
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: The Beatson West of Scotland Cancer Centre
city: Halifax
country: United Kingdom
facility: Calderdale Royal Hospital
city: Harrogate
country: United Kingdom
facility: Harrogate District Hospital
city: Huddersfield
country: United Kingdom
facility: Huddersfield Royal Infirmary
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
city: Kettering
country: United Kingdom
facility: Kettering General Hospital
city: Kingston Upon Thames
country: United Kingdom
facility: Kingston Hospital
city: Lancaster
country: United Kingdom
facility: University Hospitals of Morecambe Bay
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Livingston
country: United Kingdom
facility: St John's Hospital
city: London
country: United Kingdom
facility: Barnet and Chase Farm Hospitals
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
city: London
country: United Kingdom
facility: St George's Hospital
city: London
country: United Kingdom
facility: University College London
city: Maidstone
country: United Kingdom
facility: Maidstone and Tunbridge Wells NHS Trust
city: Manchester
country: United Kingdom
facility: North Manchester General Hospital
city: Manchester
country: United Kingdom
facility: The Christie Hospital
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Melrose
country: United Kingdom
facility: Borders General Hospital
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes University Hospital
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Nuneaton
country: United Kingdom
facility: George Eliot Hospital NHS Trust
city: Penarth
country: United Kingdom
facility: University Hospital Llandough
city: Poole
country: United Kingdom
facility: Poole General Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
city: Redhill
country: United Kingdom
facility: East Surrey Hospital
city: Rhyl
country: United Kingdom
facility: Glan Clwyd
city: Shrewsbury
country: United Kingdom
facility: Royal Shrewsbury Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Stockton-on-Tees
country: United Kingdom
facility: University Hospitals of North Tees and Hartlepool
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
city: Wakefield
country: United Kingdom
facility: Mid Yorkshire -Pinderfields Hospital
city: Warwick
country: United Kingdom
facility: Warwick Hospital
city: Wigan
country: United Kingdom
facility: Royal Albert Edward Infirmary
city: Worcester
country: United Kingdom
facility: Worcestershire Acute Hospitals NHS Trust
Study officials:
affiliation: Royal Marsden NHS Foundation Trust
name: Stephen Johnston
role: PRINCIPAL_INVESTIGATOR
References: