Breast Cancer oestrogen positive (ER+) and HER 2 negative Cancer
Conditions
Interventions
Arm A: Capivasertib (AZD5363) orally 400mg twice a day on Days 1 to 4 and Days 8 to 11 of a 14-day treatment period between diagnosis and starting standard of care treatment (surgery or neoadjuvant ch
Sponsors
Cambridge University Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
Female
Age
18 Years to 79 Years
Inclusion criteria
Inclusion criteria: 1. Female sex as assigned at birth 2. Aged between 18 and 79 years 3. Post-menopausal 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 5. ER-positive, HER2-negative invasive breast cancer 6. Intermediate or high-risk of breast cancer recurrence (grade 2 or 3 and Ki67 =10%) 7. Clinical stage T1c-4, NX or N0-N3, M0 (primary breast cancer =15mm) 8. Adequate bone marrow, renal and hepatic function 9. Capable of giving written informed consent
Exclusion criteria
Exclusion criteria: 1. Metastatic , inoperable locally advanced or recurrent disease 2. History of another primary malignancy except for malignancy treated with curative intent 3. Persistent toxicities caused by previous anticancer therapy, excluding alopecia 4. Diabetes mellitus type 1 5. Diabetes mellitus type 2 6. Haemoglobin =7.0% at screening 7. Some cardiac conditions as: mean resting QT interval at screening, arrhythmia, history of QT prolongation associated with medications that required discontinuation of that medication, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives 8. Hypotension at screening 9. Known HIV infection that is not well controlled 10. Known active hepatitis B or C infection 11. Known active tuberculosis infection 12. Known contraindication or inability to tolerate MRI 13. Known hypersensitivity or contraindications to aromatase inhibitors, capivasertib or any of the excipients of exemestane or capivasertib 14. Received any prior treatment for either this breast cancer or a previous breast cancer diagnosis 15. Prior exposure to any chemotherapy or anti-cancer agents without appropriate washout period before randomization/enrolment 16) Hormone therapy including hormone replacement therapy (HRT) use in the 6 months prior to screening 16. Radiotherapy within 14 days prior to the first dose of study intervention 17. Major surgical procedure or significant traumatic injury within 28 days of the first dose of capivasertib 18. Previous treatment in the AKTivate study 19. Participation in another clinical study with a study intervention or investigational medicinal device administered in the 28 days prior to first dose of study intervention or concurrent enrolment in another clinical study 20. Women of childbearing potential, women who are currently pregnant or breastfeeding, women who are planning to become pregnant, or women who are lactating during the study period 21. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements 22. Body mass index < 18.5 kg/m² at the time of screening
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. To determine whether the combination of capivasertib and exemestane, administered over two weeks, demonstrates target engagement that can be seen using hyperpolarized 13C MRSI techniques following an early-stage ER+ breast cancer diagnosis and before surgery 2. Target-product engagement of capivasertib +/- exemestane will be assessed by the reduction in the hyperpolarized 13C-labelled lactate/pyruvate (LAC/PYR) ratio between baseline and following at least ten days after initiation of capivasertib | — |
Secondary
| Measure | Time frame |
|---|---|
| At baseline (before treatment starts), at the last day of the medicines treatment and also at surgery (for some of the endpoints): 1. Effects on tumour proliferation will be assessed by Ki67 IHC, measuring the percentage change (%) between baseline, following at least ten days after initiation of capivasertib and at surgery 2. Changes in the hyperpolarized 13C-labelled lactate: pyruvate ratio between baseline and following at least ten days after initiation of capivasertib will be correlated with alterations observed in tumour proliferation markers during the same time frame 3. Changes in the hyperpolarized 13C-labelled lactate: pyruvate ratio, Ki67 as well as any relevant biomarker changes between baseline and following at least ten days after initiation of capivasertib will be compared between the two arms 4. A subgroup analysis is planned to assess changes in the hyperpolarized 13C-labelled lactate: pyruvate ratio, Ki67 as well as any relevant biomarker changes between baseline and following at least ten days after initiation of capivasertib in PI3K/AKT/PTEN pathway-altered tumours and non-altered tumours. Tumours will be categorised on the basis of whole-genome sequencing results 5. Change in FOXM1 status will be measured via its effects on LDHA expression using MRSI of hyperpolarized [1-13C] pyruvate metabolism 6. Safety and tolerability of capivasertib +/- exemestane will be assessed using the incidence of Serious Adverse Events (SAEs) and the incidence of Adverse Events (AEs), measured according to CTCAE v5.0 criteria | — |
Countries
England, United Kingdom
Outcome results
None listed