Clinical Trials Register

Summary
EudraCT Number:	2019-003897-24
Sponsor's Protocol Code Number:	ICRCTSU/2019/10068
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2020-06-25
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2019-003897-24

A.3

Full title of the trial

PreOperative Endocrine Therapy for Individualised Care with Abemaciclib

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

POETIC-A: PreOperative Endocrine Therapy for Individualised Care with Abemaciclib

A.3.2

Name or abbreviated title of the trial where available

POETIC-A

A.4.1

Sponsor's protocol code number

ICRCTSU/2019/10068

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	The Institute of Cancer Research
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Eli Lilly and Company
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	The Institute of Cancer Research
B.5.2	Functional name of contact point	POETIC-A trial manager
B.5.3	Address:
B.5.3.1	Street Address	ICR-CTSU, 15 Cotswold Road
B.5.3.2	Town/ city	Sutton
B.5.3.3	Post code	SM2 5NG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02087224264
B.5.5	Fax number	02087707876
B.5.6	E-mail	POETIC-A-icrctsu@icr.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Verzenios
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly Nederland B.V.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Verzenios
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	abemaciclib
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	50 to 150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Non-metastatic operable invasive ER+ HER2- breast cancer in post-menopausal women

E.1.1.1

Medical condition in easily understood language

Early stage breast cancer in post-menopausal women

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10006187
E.1.2	Term	Breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The principal research objective is to confirm whether a new drug called abemaciclib given in combination with standard endocrine therapy is more effective than giving standard endocrine therapy alone in preventing breast cancer coming back

E.2.2

Secondary objectives of the trial

The secondary objectives are;
1) to find out if particular groups of patients based on their tumour biology are more suitable for treatment with abemaciclib;
2) to compare patient reported quality of life in patients receiving combination treatment with abemaciclib compared to those receiving standard adjuvant endocrine therapy (ET) alone
3) to provide an estimate of the cost-effectiveness of combination treatment with abemaciclib in comparison with standard adjuvant ET alone
4) To assess the safety and tolerability of abemaciclib combined with ET compared to standard adjuvant ET alone

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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 analysis has been performed by the central laboratory and result 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 >/=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.

E.4

Principal exclusion criteria

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.

E.5 End points

E.5.1

Primary end point(s)

Time to tumour (local or distant disease) recurrence (TTR)

E.5.1.1

Timepoint(s) of evaluation of this end point

Relapse will be reported throughout the trial. Primary analysis will be triggered once a median of 5 years has been reached.

E.5.2

Secondary end point(s)

• Relapse-free-survival
• Time to distant recurrence
• Breast cancer specific survival
• Overall survival
• Patient reported quality of life assessed using EQ5D*
• Cost-effectiveness (incremental cost per QALY)*
• Grade3/4 Adverse events, SAEs and hospitalisations assessed by CTCAEv5
• Treatment related deaths

*Quality of life and health economics sub-studies will be set up after the main trial is open

E.5.2.1

Timepoint(s) of evaluation of this end point

Relapse-free-survival; time to distant recurrence; breast cancer specific survival; overall survival will be evaluated once a median of 5 years has been reached.

Patient reported quality of life and cost-effectiveness will be assessed at 1, 2, and 5 years.

Grade3/4 Adverse events, SAEs and hospitalisations will be assessed throughout the treatment period (up to 30 days post last dose).

Treatment related deaths will be assessed throughout the trial.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The study end date is deemed to be the date of last data capture.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1