POETIC - A

INCLUSION CRITERIA FOR THE REGISTRATION STAGE

1. Postmenopausal women defined as:

1a. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

or

1b. Documented bilateral oophorectomy.

2. Diagnosed operable invasive breast cancer with a palpable tumour of any size or an estimated invasive tumour size > = 1.5cm by imaging (ultrasound/MRI/mammogram) excluding those who are grade 1 and /or lobular histological type on diagnostic biopsy.

3. Tumour ER positive and HER2 negative. ER positivity is defined as > = 1% cells staining positive (or

equivalent Allred Score of ER > = 3 out of 8). HER2 negativity will be defined as per the 2018 ASCO/CAP updated guidelines.

4. Baseline Ki67 and/or clinical pathological factors which predict for a high (20%) 5-year risk of

relapse with AI alone (see Appendix 2)

4a. Baseline Ki67 > = 20% measured at the local site

or

4b. Presence of clinicopathologic factors that have been previously shown to predict (> 50% chance) patients with Ki67 > = 8% after 2 weeks’ AI, defined as one or more of the following

§ grade 3

§ clinical/radiological tumour size > 5cm

§ PgR negative

§ PgR unknown AND evidence of Vascular Invasion

5. No evidence of metastatic spread by standard assessment according to local guidelines.

6. Written informed consent to enter the registration stage of the trial and to donation of tissue (fresh tissue and surplus tissue from diagnostic procedures) and blood samples.

7. No medical condition or other factor likely to preclude entry to randomised stage of the study if eligible e.g. patient would not be suitable to receive abemaciclib due to concomitant medications or medical history.

8. 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.

INCLUSION CRITERIA FOR THE RANDOMISATION STAGE

1. Patient previously consented and registered for screening component of POETIC A.

2. Centrally confirmed Ki67 > = 8% following 2 weeks of AI.

3. Aromatase Inhibitor Resistant-CDK4/6 Inhibitor Sensitive (AIR-CIS) signature has been derived in the central laboratory and confirmed to ICR-CTSU.

4. Patient must have undergone definitive surgery for the primary breast tumour with clear radial margins as judged by the multidisciplinary team.

5. Surgical staging of the axilla must have been undertaken by sentinel node biopsy, axillary sampling or dissection.

6. Adjuvant chemotherapy, if prescribed, must have been completed prior to randomisation 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 randomisation. A washout period of a minimum of 28 days from day 1 of last cycle of treatment is required.

7. Adjuvant radiotherapy, if prescribed, must have been completed prior to randomisation, 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 randomisation.

8. The patient should be randomised within 6 months of commencement of adjuvant endocrine therapy.

9. The patient is able to swallow oral medications.

10. The patient has adequate organ function for all of the following criteria defined as;

ANC > / = 1.5 × 109/L (G-CSF / blood tranfusions cannot be administered to meet this ANC eligibility criterion)

Platelets > / = ³ 100 × 109 / L

Hemoglobin > / = 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

11. The patient intends to take adjuvant endocrine therapy for at least 5 years.

12. The patient has given written informed consent prior to any study-specific procedures (for the randomised intervention stage) 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. 

EXCLUSION CRITERIA FOR THE REGISTRATION PHASE

1. Men and pre/perimenopausal women.

2. Grade 1 tumours

3. Invasive lobular carcinoma.

4. Concurrent use (defined as use within 4 weeks prior to diagnostic tissue sample being taken) of HRT or any other oestrogen-containing medication (including vaginal oestrogens).

5. Prior endocrine therapy for breast cancer or breast cancer prevention.

4. Evidence of metastatic disease.

6. Locally advanced breast cancer not amenable to surgery.

7. Bilateral breast cancer.

8. Multiple unilateral tumours with different ER/PgR/HER2 status, grade or type (e.g. ductal vs lobular) i.e. anything that suggests two or more different cancers. Multifocal disease with homogenous ER/PgR/HER2 status, grade and type is allowed if at least one lesion is palpable or at least 1.5cm on ultrasound; the largest lesion should be used for sample collection and CRF completion.

9. 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.

10. Any invasive malignancy diagnosed within previous 5 years (other than non-melanoma skin cancer or cervical carcinoma in situ).

11. Any other medical condition likely to exclude the patient from subsequent randomisation stage. (See exclusion criteria: Eligibility for Randomisation).

EXCLUSION CRITERIA FOR THE RANDOMISATION STAGE

1. Patient has received prior CDK4 / 6 inhibitor.

2. 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.

3. The patient has serious/or uncontrolled pre-existing medical condition(s) 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, 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).

4. The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, 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 eligible.

5. The patient has active systemic bacterial infections (requiring 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). Screening is not required for enrolment. 

Research Nurse: Emma Davies (Ext No. 55649) Emma.Davies16@nhs.net

Administrator: Arun Prakash